Solid State Chemistry Of Abiraterone Acetate And Vitamin K₃

The physicochemical properties of solid materials are not only related to their chemical structures,but also affected by factors such as molecular conformation,intermolecular interactions and packing patterns.A compound may exist in various solid forms,such as polymorphs,amorphous forms,salts,cocrystals and so on.Differences in the conformation or packing pattern of molecules can significantly affect their physicochemical properties,such as melting point,hygroscopicity,solubility,dissolution properties,stability and so on.Crystal engineering has been widely applied in various fields,especially in the pharmaceutical field.The physicochemical properties of the API can be effectively improved by different solid forms without changing the chemical structure.In this dissertation,solid chemistry was conducted on the anti-prostate cancer drug abiraterone acetate（ABA）,its metabolic active compound abiraterone（AB）and vitamin K₃,including their polymorphs,amorphous forms and multicomponent crystal forms.In the study of AB and ABA,we focused on their problems of poor dissolution performance and low bioavailability.On the one hand,the strategy of multicomponent crystal forms was applied to improve the pharmaceutical properties of AB and ABA.It is proved by in vivo pharmacokinetic experiments that multicomponent crystal forms can effectively improve the bioavailability of AB and ABA.On the other hand,it was found that amorphous system of ABA-TAA could be quickly and efficiently prepared by mechanical method.Furthermore,the solid dispersion of this amorphous system was studied.In the study of the polymorphism of vitamin K₃,we obtained an anhydrous form and two different hydrates of vitamin K₃.Furthermore,we have established the transformation relationships between the three solid forms of vitamin K₃ through comprehensive solid-state characterizations.The newly discovered anhydrous Form A significantly delayed the degradation of vitamin K₃.The relationship between the crystal structure and the chemical stability was discussed based on the degradation reaction mechanism.In chapter 1,the common pharmaceutical solid forms and their preparation methods were briefly described.The effects of solid forms on different physicochemical properties of drugs were reviewed,with emphasis on the application of solid forms in solubilization of poorly soluble drugs.The chapter arrangement of this dissertation was summarized.In chapter 2,multicomponent crystal forms of AB were uncovered.In this section,we designed and prepared four salts and three cocrystals of AB based on crystal engineering strategy.The single crystal structures of the above seven multicomponent crystal forms were obtained by SCXRD,and structural analysis and solid-state characterizations were carried out.The in vitro dissolution properties of the edible multicomponent crystal forms were compared,and the apparent solubility of all salts in both dissolution media（p H 2.0 and p H 4.5）were shown to be improved compared to the AB raw material.Among them,AB-OA showed the largest solubility,which is 1.7times and 1.4 times that of AB raw material in p H 2.0 and p H 4.5 solutions,respectively.At the same time,the results of IDR indicated that the dissolution rate of AB also changed after salt formation.Similarly,AB-OA had the most significant improvement on IDR,which is 2.6 times and 2.2 times that of AB in p H 2.0 and p H 4.5 solutions,respectively.The results of in vivo pharmacokinetic experiments in rats were consistent with the in vitro dissolution.Compared with the current marketed solid form（ABA）,AB-OA showed higher exposure,where C_max was increased by 40%,AUC_0-t increased by 25%.Therefore,AB-OA can be a promising solid form for clinical application of AB.In chapter 3,two salts and nine cocrystals of ABA were designed and prepared by taking advantage of the robust interactions of COOH-N_pyridine and OH-N_pyridine.The single crystal structures of the above 11 multicomponent crystal forms were obtained by SCXRD,which confirmed the existence of the expected synthons in the crystal structures.The comprehensive solid-state characterizations were carried out.The crystallinity and thermal behaviors were elucidated by XRPD and thermal analysis.Intermolecular interactions in multicomponent crystal forms were analyzed by FT-IR.Their hygroscopicity and humidity stability were tested by DVS.In dissolution experiments,we discovered the gelation of ABA in simulated gastric fluid（SGF）.Through a series of solid-state chemistry studies,we found that the gelation is due to the conversion of ABA to hydrochloride in SGF.The specific crystal morphology of hydrochloride makes it tend to form a gel-like substance in aqueous solution,thereby delaying the dissolution of ABA.The results of in vitro dissolution experiments showed that ABA-TAA cocrystal could significantly improve the solubility and dissolution rate of ABA,and delay the formation of gel-like substances to the greatest extent.The polar and nonpolar interactions between ABA and ABA-TAA crystal structure were compared by Hirshfeld surface analysis,and the results showed that ABA-TAA has stronger hydrophilcity.Finally,in vivo pharmacokinetic results in beagle dogs showed that AUC_0-t of the ABA-TAA cocrystal formulation was approximately 1.7 times that of the commercially available ABA tablets.In this chapter,the correlation of the crystal structure,in vitro dissolution properties and in vivo bioavailability were confirmed.For the first time,the bioavailability of ABA was successfully improved by cocrystallization technology.In chapter 4,we successfully prepared the stable amorphous ABA by mechanical method for the first time based on the difference in crystal structure between the ABA raw material and ABA-TAA cocrystal.Combined with Gordon-Taylor equation and FT-IR analysis,it was found that ABA-TAA-AM is a disordered state in the long-range,but in the short-range,there is still an intermolecular interaction between the two components,which effectively improves the physical stability of the amorphous system.ASD studies were carried out based on this amorphous form.The stability and dissolution properties of the ASDs prepared based on four carrier materials（PVP-K30,HPMC,Soluplus and Eudragit L100）were investigated.It was found that Soluplus as the carrier material could significantly increase the glass transition temperature and improve the stability of the amorphous system.At the same time,Soluplus could effectively improve the solubility of the amorphous system and has a good ability of crystallization inhibition.In order to further improve the absorption of the ASD,the effects of three excipients（SDS,DEC and TPGS）on the pharmaceutical properties of the formulation were investigated through in vitro dissolution and permeability experiments.The effects of the type and amount of excipients in the formulation on the absorption of ASD were clarified through in vivo pharmacokinetic experiments in rats.Finally,the C_max and AUC_0-tof the ASD formulation were 3.0 times and 2.9 times those of the commercially available ABA tablets,respectively.This study provided a potential ASD with high drug loading,high bioavailability and great physical stability for the clinical application of ABA.In chapter 5,the strategy of polymorphism is proposed to delay the degradation of vitamin K₃ by changing the conformation and packing mode of molecules.An anhydrous Form A,dihydrate HA and 2.5 hydrate HB of vitamin K₃ were discovered.The single crystal structures of these three solid forms were obtained by SCXRD.Comprehensive solid-state characterizations were performed,and the transformation relationships between the three solid forms were confirmed.The chemical stability results of the three solid forms of vitamin K₃ indicated that the newly discovered anhydrous Form A exhibited great chemical stability.Combining the crystal structures of the three solid forms and the degradation mechanism（β-elimination reaction）of vitamin K₃,we supposed that,on the one hand,the compact packing pattern of Form A hinders the movement of molecules in the crystal lattice and makes the degradation more difficult to occur.On the other hand,the molecular conformation of Form A is more unfavorable forβ-elimination reaction and improves its stability.In addition,phase transformation was not undergone in Form A with aluminum-plastic package under accelerated condition.In conclusion,anhydrous Form A can be a promising solid form in the application of vitamin K₃.