Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and he...Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.展开更多
Nonexchangeable K （NEK） is the major portion of the reserve of available K in soil and a primary factor in determining soil K fertility. The questions of how much NEK is in soils and how to quantify total NEK in soi...Nonexchangeable K （NEK） is the major portion of the reserve of available K in soil and a primary factor in determining soil K fertility. The questions of how much NEK is in soils and how to quantify total NEK in soils are so far still unclear due to the complicated effects of various minerals on K fixation. In this study, the NEK in 9 soils was extracted with sodium tetraphenylboron （NaBPh4） for various time periods longer than 1 d. The results showed that the NEK extracted by NaBPh4 gradually increased with time, but showed no more increase after the duration of extraction exceeded 10 20 d. As the temperature increased from 25 to 45 ~C, the duration to obtain the maximum extraction of NEK was reduced from 20 to 10 d, and the maximum values of NEK released at both temperatures was almost the same for each soil. The maximum NEK （MNEK） of the 9 soils extracted by NaBPh4 varied from 3074 to 10081 mg kg-1, accounting for 21% 56% of the total soil K. There was no significant correlation between MNEK released by NaBPh4 and other forms of K, such as NH4OAc-extracted K, HNO3-extracted K and total K in soils, which indicates that NEK is a special form of K that has no inevitable relationship to the other forms of K in soils. The MNEK extraction by NaBPh4 in this study indicated that the total NEK in the soils could be differentiated from soil structural K and quantified with the modified NaBPh4 method. The high MNEK in soils made NEK much more important in the role of the plant-available K pool. How to fraetionate NEK into different fractions and establish the methods to quantify each NEK fraction according to their bioavailability is of great importance for future research.展开更多
基金supported in part by an Ontario Research Fund-Research Excellence(ORF-RE)grant(Ontario,Canada)in partnership with Patheon by Thermo Fisher Scientific,Natural Sciences and Engineering Research Council(NSERC)of Canada Discovery Grant and Equipment Grants to Xiao Yu Wu,University of Toronto(Canada),Leslie Dan Faculty of Pharmacy Dean's Fund to Jamie Anne Lugtu-Pe,University of Toronto(Canada),Mitacs Accelerate Internship sponsored by Candoo Pharmatech Company Inc.to Xuning Zhang(Canada),NSERC CREATE ContRoL program support to Sako Mirzaie and Hao Han R.Chang(Canada),Ontario Graduate Scholarship(OGS)to Hao Han R.Chang(Canada),and Pharmaceutical Sciences graduate department scholarships to Hao Han R.Chang and Kuan Chen,University of Toronto(Canada).
文摘Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.
基金supported by the Special Fund for Agro-scientific Research in the Public Interest of China (No.201203013)the National Natural Science Foundation of China(Nos.40971176 and 40201027)the International Potash Institute(IPI) China Project
文摘Nonexchangeable K （NEK） is the major portion of the reserve of available K in soil and a primary factor in determining soil K fertility. The questions of how much NEK is in soils and how to quantify total NEK in soils are so far still unclear due to the complicated effects of various minerals on K fixation. In this study, the NEK in 9 soils was extracted with sodium tetraphenylboron （NaBPh4） for various time periods longer than 1 d. The results showed that the NEK extracted by NaBPh4 gradually increased with time, but showed no more increase after the duration of extraction exceeded 10 20 d. As the temperature increased from 25 to 45 ~C, the duration to obtain the maximum extraction of NEK was reduced from 20 to 10 d, and the maximum values of NEK released at both temperatures was almost the same for each soil. The maximum NEK （MNEK） of the 9 soils extracted by NaBPh4 varied from 3074 to 10081 mg kg-1, accounting for 21% 56% of the total soil K. There was no significant correlation between MNEK released by NaBPh4 and other forms of K, such as NH4OAc-extracted K, HNO3-extracted K and total K in soils, which indicates that NEK is a special form of K that has no inevitable relationship to the other forms of K in soils. The MNEK extraction by NaBPh4 in this study indicated that the total NEK in the soils could be differentiated from soil structural K and quantified with the modified NaBPh4 method. The high MNEK in soils made NEK much more important in the role of the plant-available K pool. How to fraetionate NEK into different fractions and establish the methods to quantify each NEK fraction according to their bioavailability is of great importance for future research.
