1.Introduction

Sulconazole,1-[2,4-dichloro-β-[(4-chlorobenzyl)thio]phenethyl]-imidazole,is an azole antifungal drug belonging to the family of the imidazole class,and is typically used as a topical antifungal cream or solution for the treatment of dermatomycoses,pityriasis versicolor,and cutaneous candidiasis[1].Sulconazole nitrate was among the drug substances that were undergoing United States Pharmacopeia(USP)monograph modernization[2].The USP sulconazole nitrate monograph describes an HPLC procedure for assay,but lacks any organic impurity procedures[3].Sulconazole nitrate is currently not included in other major pharmacopeias.

面向5G毫米波通信系统的本振源设计与实现………………………………………………胡蒙筠，周健义 24-3-21

综上所述，年龄小于60岁窦性心动过缓患者的DC值增高，迷走神经张力增高。DC值和HRV指标都能反映心脏自主神经功能，DC作为一项独立定量评估人体迷走神经张力大小的新技术，它不易受外界环境的干扰，对窦性心动过缓患者的评估价值较高，值得进一步探讨。

A literature search indicated that limited information is available regarding the stability and chromatographic analysis of this drug substance.HPLC methods have been reported for the analysis of sulconazole in biological samples or drug products[4–7],but sulconazole related compounds were not included for method development or evaluation.In terms of stability studies,comprehensive degradation studies under various stress conditions have not been reported.Chen et al.[8]investigated the kinetics of oxidation of sulconazole with peracetic acid and hydrogen peroxide;sulconazole sulfoxide and sulfone were assumed to be the oxidation products.Iwasawa et al.[9]reported the pharmacological studies of the metabolites of sulconazole and highlighted the liability of the molecule towards oxidative conditions.However,no structural information was disclosed in either of those papers.

（3）虚增企业利润。因为我国企业目前实行的是权责发生制，以取得收款权利付款责任作为记录收入或费用的依据，因此企业通过赊销所获得的收入全部记入当期收入，但资金不一定是本期流入企业，因此赊销在一定程度上虚增了企业的收入，增加了企业的财务风险。

Oxidation of organic sulfides(thioethers)to sulfoxides is an important degradation and metabolic pathway for a variety of sulfurcontaining pharmaceutical agents,such as montelukast[10],ranitidine[11],penicillin[12],pergolide[13],and methionine-or cysteine-containing peptides[14].The oxidation process could be complicated as N-or S-oxidation might occur[11],and over-oxidation of a sulfoxide to the corresponding sulfone is frequently a competing reaction[15].To gain a better understanding of the stability of sulconazole nitrate and incorporate the impurity profile into USP monographs,it is critical to differentiate the oxidation pathways and conf i rm the structures of the degradation products[16].

Here we report the structural determination of a major degradation product of sulconazole nitrate,sulconazole sulfoxide,which was generated under oxidative conditions.In addition,this material was subsequently employed as an impurity reference for compendial procedure development and validation.The monograph modernization efforts have eventually culminated in an off i cial compendial procedure and a newly introduced impurity,sulconazole related compound A[17,18].

2.Material and methods

2.1.Chemicals and reagents

The drug substance sulconazole nitrate was obtained from the USP Reference Standard.Commercial samples of sulconazole nitrate were purchased from Sigma-Aldrich(St.Louis,MI,USA),Spectrum Chemical(New Brunswick,NJ,USA),Glentham Life Sciences(Corsham,UK),and Erregierre(Sovere,Italy).Hydrochloric acid(37%),glacial acetic acid(≥99.7%),sodium hydroxide solution(10 N,J.T.Baker),trifluoroacetic acid(TFA,99.5%,Acros Organics),ammonium acetate(LC/MS),methanol(LC/MS),and acetonitrile(HPLC and LC/MS)were purchased from Fisher Scientific(Waltham,MA,USA).Hydrogen peroxide(～30%)was obtained from Sigma-Aldrich.Water was purif i ed with a Milli-Q plus system from Millipore(Bedford,MA,USA).

2.2.1.UHPLC/HPLC

2.2.Instrument and analytical parameters

玉米植株正常成熟时苞叶逐渐干枯、松散，子粒“乳线”消失，基部形成黑层，显出子粒特有光泽，含水率一般在3O%左右。目前普遍存在的问题是过早收获，含水率偏高，容重低.霉粒、破损粒多，商品品质差，既影响产量，又影响品质。要等到玉米充分成熟后收获，适当晚收，利于玉米产量增加和品质提高。

UHPLC–UV analyses were performed on an Agilent Infinity 1290 UHPLC system(Santa Clara,CA,USA).Separation was carried out on an Acquity BEH C18column(2.1 mm × 100 mm,1.7 μm)from Waters(Milford,MA,USA)using a mobile phase system consisting of mobile phase A:methanol and ammonium acetate buffer(pH 5.0;0.1 mM)(20:80,v/v);and mobile phase B:methanol and acetonitrile(40:60,v/v).Analyses were performed at ambient temperature with a flow rate of 0.5 mL/min and a gradient elution varied according to the following program:0 min,40%B;8min,90%B;8.1 min,40%B;and 10 min,40%B.UV detection wavelength was set at 230 nm.The injection volume was 5μL.

HPLC–UV analyses were performed on a Waters Alliance 2695 HPLC system using a Waters Atlantis C18column(4.6 mm×150 mm,5 μm)and a mobile phase system consisting of 0.05%TFA in water and acetonitrile.Separations were achieved at ambient temperature with a f l ow rate of 1.0 mL/min and an isocratic program of 0.05%TFA in water and acetonitrile(50:50,v/v).UV detection wavelength was set at 210nm.The injection volume was 10μL.

3.4.1.NMR studies of sulconazole and sulconazole sulfoxide

Waters Empower 2 for chromatography software was used for instrument operation control and data acquisition and processing.

2.2.2.NMR analysis

NMR experiments were recorded using a Bruker Avance III NMR Spectrometer(Billerica,MA,USA)with operating frequencies of 600.13 MHz(1H)and 150.90 MHz(13C).Samples were dissolved in DMSO-d6and all NMR spectra were recorded at 25°C.Chemical shifts were reported in ppm down field from tetramethylsilane(TMS,δ=0)as the internal reference.

2.2.3.LC–MS/MS analysis

The LC–MS/MS was performed on an Agilent 6540 UHD Accurate-Mass QTOF LC–MS using an Agilent 1290 UHPLC as an inlet with UV detection at 210nm prior to the mass spectrometer.Data acquisition and analysis were performed using Agilent MassHunter software.ESI was used in positive ion mode.Except for the injection volume(2μL),LC conditions were the same as those used for UHPLC–UV analysis in Section 2.2.1.The mass spectrometer was tuned in 2 GHz extended dynamic range mode(24,350 FWHM resolution at m/z 1521.9715)for accurate mass analyses.Mass accuracy was less than 0.2 ppm for reference masses across the mass range of m/z 100–1700.The mass range analyzed was m/z 100–1200.

2.3.Solution and sample preparation for UHPLC method

A solution of water and methanol(60:40,v/v)was used as the diluent.A resolution solution was prepared by dissolving sulconazole nitrate and sulconazole sulfoxide in the diluent to give a solution having a concentration of 0.15 mg/mL for sulconazole and 1.5μg/mL for sulconazole sulfoxide.The standard solution was prepared at a concentration of 1.5 μg/mL for sulconazole and sulconazole sulfoxide.The sample solution at a concentration of 1.5 mg/mL was prepared by dissolving a sulconazole nitrate bulk material in the diluent.

3.Results and discussion

3.1.HPLC method development

The LC–MS analysis showed that the masses of sulconazole and a major oxidation product were m/z 397.0094 and 413.0045,respectively(Fig.S1).The major oxidative degradant showed a protonated molecule that had a delta of 16amu difference from sulconazole,suggesting a single N or S oxidation.A minor ion at m/z 428.9997 with a mass change from sulconazole of 32amu indicated that a secondary degradation,the possible oxidation of sulfoxide to sulfone,or S-oxidation followed by N-oxidation,might occur.

An HPLC method was also developed as a guiding method for subsequent preparative HPLC operation(Section 2.2.1).Complete separation was achieved for sulconazole and the major degradant using a Waters Atlantis column and a mobile phase of acetonitrile and 0.05%TFA.Although the method did not provide sufficient resolution for the major degradant and the secondary degradant,our initial scale-up experiments on preparative HPLC revealed that the lack of resolution did not pose a problem for the overall purification.

3.2.Forced degradation of sulconazole nitrate

Forced degradation studies of sulconazole nitrate were performed under thermal,thermal and humidity,photolytic,hydrolytic(acid and base),and oxidative conditions(Fig.1).The degradation was monitored and analyzed using the UHPLC method with UV and MS detection and both detection techniques revealed that degradation of sulconazole only occurred under oxidative conditions(Table S1 and Fig.S1).In addition to the major degradant,a trace amount of secondary degradant was also detected when the stress time was prolonged or the concentration of the oxidant was increased(Fig.2).PDA peak purity testing and LC–MS were performed for the sulconazole peak and no co-elution of impurities was detected.

宫颈腺癌组和对照组手术时间和术中出血量比较，差异无统计学意义(P＞0.05)，两组患者在手术过程中均无肠管、大血管、神经及周围脏器等手术损伤。术后宫颈腺癌组1例患者出现切口脂肪液化、积极换药后延期愈合，1例患者术后2月出现膀胱阴道瘘、经保守治疗后好转，两组患者切口甲级愈合率及并发症发生率比较，差异无统计学意义(P＞0.05)。见表1

Fig.1.Oxidative stress of sulconazole nitrate.

Fig.2.Overlaid chromatograms of oxidative stress of sulconazole nitrate(from bottom to top:chromatogram of sulconazole,chromatograms of sulconazole under oxidative stress for 3 days and 12 days).

In light of the structural similarities between sulconazole and econazole(another azole antifungal drug),the mobile phases used in the European Pharmacopeia econazole monographs(econazole and econazole nitrate)were directly adopted as a starting point for UHPLC method development[19].Column optimization led to the identification of ethylene bridged hybrid(BEH)C18silica as the choice of stationary phase.The effective chromatographic separation between sulconazole and the major degradant was achieved using a Waters Acquity BEH column(2.1mm×100 mm,1.7 μm)and a mobile phase of methanol-ammonium acetate buffer and methanol-acetonitrile in a gradient elution.In addition to the separation of the major degradant and sulconazole,the method was also capable of separating the major degradant from a minor secondary degradant with a resolution of 1.4.

李光北得的是早期股骨头坏死，虽然治好，但再不能干重活，只好辞了职。青瓷想了几天，决定开个水果店，进货什么的她负责，李光北只要看店就好。

3.3.Synthesis and preparative isolation of the degradation product

The scale-up oxidation experiment was performed in a concentrated sample solution using 30%hydrogen peroxide.Complete conversion of sulconazole nitrate to the major degradant was achieved within 20 h(Fig.S2).The experiment was halted when an over-oxidation started to occur.As the reaction proceeded to 100%conversion,the challenge of the purification step was the removal of the minor degradant,which had a retention time close to that of the major peak.

The injection and loading amount were carefully evaluated on an analytical column(Waters Atlantis C18,4.6 mm×150 mm,5μm)to ensure the sufficient separation of the two peaks on the similar preparative column(Prep-C18,20.1 mm × 150 mm,5 μm)while maintaining separation efficiency.To this end,the heartcutting technique was applied and multiple injections of the crude reaction mixture at an appropriate concentration were performed(Fig.S3).The isolated compound was re-analyzed on both analytical HPLC and UHPLC to confirm the identity and purity(Fig.S4).The degradant was isolated as a colorless oil in 93%yield and 98%purity based on HPLC.

3.4.Structural characterization of the major degradation product

Preparative chromatography was performed on a Waters semipreparative HPLC system consisting of a 2335 quaternary gradient module,a 2998 photodiode array detector,a 2707 autosampler,and a Waters fraction collector III.Separations were carried out on an Agilent Prep-C18column(20.1 mm × 150 mm,5μm)using a mobile phase system consisting of 0.05%TFA in water and acetonitrile(65:35,v/v).The f l ow rate was 10.0 mL/min and the run time was 13 min.UV detection was performed at 210nm.The injection volume was 0.4 mL.Fractions were collected based on time mode.

Samples of sulconazole nitrate and the isolated major degradation product were subjected to NMR spectroscopic analyses including one-and two-dimensional NMR such as gradient-selected correlation spectroscopy(gCOSY),heteronuclear singlequantum coherence(HSQC)and heteronuclear multiple bond correlation(HMBC)experiments.The NMR spectroscopic data were consistent with the proposed structures of sulconazole and sulconazole sulfoxide(Supplementary material).The1H and13C assignments were made based on characteristic chemical shifts(1D NMR)and were supported by2D NMR data.The1H and13C NMR data and proposed assignments for the two compounds are presented in Table 1 for comparison.

Direct assignments for protons of the two substituted aromatic rings were difficult due to the high degree of similarity inthe1H and13C chemical shifts.In the1H NMR spectrum,a significant chemical shift was observed for methine 5 and methylene 12 protons(Table 1).The change of the splitting pattern indicated the corresponding conformational change after the oxidation of the sulfur[24].More drastic down field shifts of methine 5 and methylene 12 were detected in the13C NMR.In contrast,negligible changes of chemical shifts(1H and13C)on the imidazole ring were observed,indicating that the N-oxidation of imidazole did not occur.Notably,a slight down field shift was detected for methylene 4 in the1H NMR,and a slight upf i eld shift was observed for the same methylene in the13C NMR.These results were in good agreement with NMR data for alkyl groups in a beta orientation to sulfur.The HMBC data showed connections between H1 and C2 and C3,H4 and C5,and H5 and C12(Fig.3).The1H and13C NMR data,in combination with the LC–MS results,provided reasonable evidence in support of the S-oxidation.However,the NMR data alone were not conclusive to differentiate sulfoxide from sulfone,the potential over-oxidation byproduct,as the influence of aliphatic sulfoxide and sulfone groups on the chemical shifts of theα,β,and γ substitutes is very similar[25,26].

[7]李勇,左连凯,刘亭立：《资产负债观与收入费用观比较研究:美国的经验与启示》，《会计研究》2005年第12期。

Table 1 Comparative1H NMR and13C NMR data of sulconazole nitrate and sulconazole sulfoxide(DMSO-d6,25°C).

a13C signals were not readily apparent in the13C NMR spectrum,and C5 and C11 were identif i ed using HMBC experimental data.

Position Sulconazole nitrate chemical shifts(ppm) Sulconazole sulfoxide chemical shifts(ppm)13C 1H No.of H multiplicity 13C 1H No.of H multiplicity 1 136.5 9.03 1H s 136.2 9.06 1H s 2 120.1 7.61 1H d,J=1.5 120.3 7.61 1H m 3 122.3 7.61 1H d,J=1.5 122.4 7.65 1H m 4 50.9 4.82,4.75 2H dd,J=18.0 46.7 5.02–5.14 2H m J=6.0 5 44.6 4.65 1H t,J=6.0 58.8a 5.06 1H m 6 133.1 7 134.3 134.5 133.3 8 129.4 7.67 1H 9 133.7 131.1 129.1 7.58 10 128.0 7.47 d,J=6.0 128.3 7.67 1H m J=2.0 11 130.5 7.57 d,J=6.0 129.7a 7.64 1H m 12 34.2 3.89,3.72 2H d,J=12.0 55.3 4.20,4.26 2H d,J=12.0 13 135.9 134.7 16 131.1 129.8 14,18 130.6 7.27 2H d,J=6.0 132.1 7.35 2H d,J=6.0 15,17 128.4 7.34 2H d,J=6.0 128.7 7.43 2H d,J=6.0

Fig.3.Key1H–13C HMBC correlations of sulconazole sulfoxide.Correlations are shown with arrows.The numbering system is based on the NMR assignments presented in Table 1.

3.4.2.LC–MS/MS studies

The MS/MS results of sulconazole nitrate were significantly different from those of sulconazole sulfoxide(Fig.S6).As expected,McLafferty-type fragmentation corresponding to the cleavage of S–CH bond was not observed.The ion g at m/z 125.0158 is predominant under similar activation conditions,suggesting that the cleavage of S–CH2bond is the favored dissociation process resulting in the stable carbocation(Fig.S7).Another main fragment ion j at m/z 183.0030 was generated as a result of the consecutive loss of imidazole and chlorobenzene,which also led to the formation of a stable benzyl thiirane methyl carbocation j.In addition,the intermediate ion h at m/z 328.9717 resulting from the loss of imidazole was also detected.

N-oxidation of the imidazole of miconazole nitrate,a similar imidazole antifungal drug,has been reported under hydrogen peroxide-mediated oxidation conditions[20].It is well-documented that both N-and S-oxidation could be competing pathways for drug substances containing both N and S sites susceptible to oxidation,such as ranitidine[21].More importantly,S-oxidation is not always inherently favored over N-oxidation[22].For instance,zofenopril was recently demonstrated to undergo N-oxidation selectively using hydrogen peroxide as an oxidant[23].On the basis of these precedents,the possibility of N-oxide products of sulconazole cannot be excluded at this stage.

The LC–MS/MS analysis was performed using the same UHPLC method(Section 2.2.1).The presence of multiple chlorine atoms in the molecules allows for more precise determination of the fragment ions based not only on the exact mass but also the isotope abundance ratio.The LC–MS spectrum of the oxidative degradant of sulconazole showed a protonated molecule[M+H]+at m/z 413.0048(Fig S5),suggesting an elemental composition of C18H16Cl3N2OS,which is consistent with the structure resulting from S-or N-oxidation.The MS/MS spectrum and possible fragmentation pathways are shown in Fig.4.The MS/MS fragmentation of the[M+H]+ion exhibited a diagnostic fragment ion at m/z239.0136(elemental composition of C11H9N2Cl2),which can be derived from the syn-elimination of alkyl sulfenic acid via a 5-membered cyclic transition state.This McLafferty-type fragmentation has been revealed as a dominant fragmentation pathway for peptides containing oxidized methionine or cysteine residues[27,28].In addition,it was verified as the most facile fragmentation for the styryl-and alkyl-propenyl sulfoxides by deuterium labeling studies[29].Mechanistically,for sulfur-containing molecules this fragmentation only occurs for sulfoxides with aβ-hydrogen atom,and it was indeed observed in numerous reported cases[30–33].The McLaffertytype fragmentation might be a characteristic fragmentation pathway for sulfoxides with aβ-hydrogen atom and could also be used here to distinguish the sulfoxide from the sulfone.Initial examination of the isotopic pattern of this fragment ion indicated that there may be overlapping ion distributions,and a possible fragment b at m/z 240.0212 resulting from a proposed sulfinyl radical cleavage may be contributing to the overall isotopic pattern(Fig.4).Another major fragment at m/z 171.9841(d)may be derived from fragment b via loss of the imidazole ring.The fragment c at m/z 205.0527 was also generated via a McLafferty-type fragmentation after dechlorination of the[M+H]+ion[34–36].In addition to major fragments,the ions at m/z 125.0147(C7H6Cl,e)and 287.9879(C11H10Cl2N2OS,f),generated from cleavage of S-CH2bond were also observed,but were much less abundant(0.05%and 0.02%,respectively),suggesting that this disassociation pathway is not favored.

粗脖子官兵很兴奋，说：“盗墓贼身上肯定有好东西，按住他，我来搜！”结果，只搜出几个铜钱，他火上来了，举起刀，就要把盗墓贼砍死。

Fig.4.(A)MS/MS spectrum of protonated molecular ion[M+H]+at m/z 413.0048 of sulconazole sulfoxide.(B)proposed fragmentation pathway.The isotope pattern of ion cluster at m/z 239.0136 matches the results of superimposition of two species of a and b as shown in the inserted frame.

As shown in Table 2,all fragmentation assignments were supported by accurate mass data.The accuracy for the masses of these ions,determined relative to the values calculated from their assigned structures,was within 5ppm error.

The comparative MS/MS studies provided compelling evidence that the oxidation occurred on the sulfur atom only,and that the sulfoxide was the primary degradant.Sulconazole sulfone is most likely the product of over-oxidation.Moreover,previous investigations on N-oxides indicated that the mass spectrum of an N-oxide is in general similar to that of parent compound[20],which is also in agreement with our conclusion in support of S-oxidation.

3.5.UHPLC method validation

With the sulconazole sulfoxide in hand,the UHPLC method was validated for specif i city,linearity,accuracy,precision androbustness.System suitability was verified by determining the%RSD of six injections of the standard solution.Retention time,tailing factor and resolution between the sulconazole and sulconazole sulfoxide were also determined(Table S2).The specif i city of the method was established by determining peak purity of sulconazole nitrate subjected to a series of stressed conditions using photodiode array detection.Linearity of the detector responses was determined at five concentration levels of sulconazole nitrate and sulconazole sulfoxide covering 0.75,1.125,1.50,1.875 and 2.25 μg/mL for each compound.To study method accuracy,recovery experiments were carried out by applying the standard addition method.Known quantities of sulconazole sulfoxide of 0.75,1.50 and 2.25 μg/mL—corresponding to 50%,100%and 150%impurity levels—were spiked into a 1.5 mg/mL sulconazole nitrate solution.Accuracy was expressed as the percentage of sulfoxide recovered by the HPLC analysis.Repeatability was studied by carrying out method precision,and determined from results of six independent injections of the 100%spiked solutions.Method robustness was evaluated by analyzing five replicate injections of the robustness solution,sulconazole nitrate(150 μg/mL)and sulconazole sulfoxide(1.5 μg/mL),under each of the varied conditions including temperatures,flow rates,buffer pH,mobile phase B initial compositions,mobile phase B final compositions,and different columns on different instruments.

Table 2 Accurate mass measurement of the molecular ions observed from the MS/MS data of sulconazole sulfoxide and sulconazole.The MS/MS spectrum of sulconazole nitrate and proposed fragmentation pathway are provided in Figs.S6 and S7.

Fragment Observed mass m/z Error in ppm[M+H]+ 413.0048 C18H16N2Cl3OS413.0043 1.21 a 239.0136 C11H9N2Cl2 239.0137 -0.42 b 240.0212 C11H10N2Cl2 240.0216 -1.67 c 205.0527 C11H10N2Cl 205.0527 0 d 171.9841 C8H6Cl2 171.9847 -3.49 e 125.0147 C7H6Cl 125.0153 -4.80 f 287.9879 C11H10Cl2N2OS287.9885 -2.08[M+H]+ 397.0089 C18H16N2Cl3S 397.0094 -1.26 g 125.0158 C7H6Cl 125.0153 4.00 h 328.9717 C15H12Cl3S 328.9720 -0.91 i 361.0315 C18H15Cl2N2S 361.0328 -3.60 j 183.0030 C9H8ClS 183.0030 0 Composition Theoretical mass m/z

The validation results are summarized in Table S3.The results demonstrated that the method is specif i c as sulconazole sulfoxide was separated from sulconazole and no interfering peak appeared at the retention time of the two peaks.Linear responses over the range of concentrations of 0.75–2.25 μg/mL were observed for both sulconazole and sulconazole sulfoxide(Fig.S8).Spike recoveries close to 100%at different levels indicated an acceptable accuracy of the method(Table S4).The low values of%RSD for method precision indicate that the method is reproducible.Finally,robustness studies showed that variations of the operating parameters did not significantly change the chromatographic profiles or the result,indicating that the method was robust under the experimental conditions(Table S5).

4.Conclusions

In summary,a systematic UHPLC study was conducted on sulconazole nitrate.The study included stress testing of sulconazole nitrate,preparative HPLC isolation of the major degradation product,structural confirmation of the degradant,and UHPLC method validation.Based on NMR and LC–MS/MS analysis,the S-oxidation of sulconazole to sulconazole sulfoxide was confirmed as the predominant degradation pathway.In addition,the generated degradation product was utilized as a reference standard for organic impurity HPLC method development and validation.This work displays a typical approach used to support USP monograph modernization.

Conflicts of interest

The authors declare that there are no conflicts of interest.

We thank USP colleagues,Doug M.Podolsky,James R.Austgen,Praveen K.Pabba,Marcela Nefliu,and Sitaram Bhavaraju for help with preparing the manuscript.

Disclaimer

Certain commercial equipment,instruments,vendors,or materials may be identified in this manuscript to specify adequately the experimental procedure(s).Such identification does not imply approval,endorsement,or certification by USP of a particular brand or product,nor does it imply that the equipment,instrument,vendor,or material is necessarily the best available for the purpose or that any other brand or product was judged to be unsatisfactory or inadequate.All product names,logos,and brands are property of their respective owners.

Appendix A.Supplementary material

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jpha.2017.12.007.

姐姐先把消息截屏下来，再把消息删除，然后把消息截屏发到她的手机上并删除消息，最后再把妈手机上的截屏给删掉，整件事看不出一点破绽。

在一般意义上，我们进一步加入非农就业时间将此模型拓展为家庭不同性别成员关于农地经营、非农就业距离和非农就业时间这三种“产品”的分工与专业化模型之后，便能推论:

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