Abaphakathi luhlobo olubaluleke kakhulu lweemveliso zeekhemikhali ezintle. Ngokwenene, zihlobo "lweemveliso ezigqityiweyo", ezisetyenziswa ngokubanzi kwi-synthesis yeyeza, i-pesticides, iingubo, iidayi kunye neziqholo.

Kwiyeza, i-intermediates isetyenziselwa ukuvelisa i-APIs.

Ke yintoni imboni ye-niche ye-pharmaceutical intermediates?

01

Oku kubizwa ngokuba ngama-pharmaceutical intermediates ngokwenene zezinye izinto zekhemikhali ekrwada okanye iimveliso zekhemikhali ezisetyenziswa kwinkqubo yokwenziwa kweziyobisi.
Umchiza, ongayifuniyo ilayisenisi yokwenziwa kweziyobisi, unokuveliswa kumzimveliso wemichiza oqhelekileyo kwaye, xa ufikelela kumanqanaba athile, unokusetyenziswa ekudityanisweni kweziyobisi.

Umfanekiso

Okwangoku, ezona ntlobo zithembisayo ze-pharmaceutical intermediate ikakhulu zilandelayo:

Nucleoside intermediates.
Olu hlobo lwe-intermediate synthesis lwamachiza alwa noGawulayo ubukhulu becala zidovudine, evela eUnited States Glaxo.
Wamkelekile kwaye uBristol-Myers Squibb uyayenza.

Iziphakathi zentliziyo.
Ngokomzekelo, i-sartans yokwenziwa isetyenziswe ngokubanzi kunyango lwe-hypertension ngenxa yempembelelo yabo epheleleyo ye-antihypertensive, imiphumo embalwa yecala, ixesha elide elisebenzayo (ukulawulwa okuzinzile koxinzelelo lwegazi kwiiyure ze-24) kunye nokukwazi ukusetyenziswa ngokudibanisa namanye ama-sartan.
Ngokwezibalo, ngo-2015, imfuno yehlabathi yesartan esebenzayo yeziyobisi (i-losartan potassium, i-olmesartan, i-valsartan, irbesartan, i-telmisartan, i-candesartan) ifikelele kwiitoni ezingama-3,300.
Iyonke intengiso yayiyi-21.063 yeebhiliyoni zeedola.

Fluorinated intermediates.
Amachiza eFluorinated adityaniswe kumaziko anjalo aphakathi akhule ngokukhawuleza kwiminyaka yakutshanje ngenxa yokusebenza kwawo okugqwesileyo. Ngo-1970, kuphela i-2% yamachiza e-fluorinated emarikeni; ngo-2013, i-25% yamachiza e-fluorinated ayekwimarike.
Iimveliso ezimele ezifana ne-fluoroquinolone anti-infective drugs, i-antidepressant fluoxetine kunye ne-antifungal fluconazole i-akhawunti ye-antifungal ye-fluconazole kwinani eliphezulu ekusebenziseni iklinikhi, phakathi kwayo i-fluoroquinolone i-anti-infective drug i-akhawunti malunga ne-15% yesabelo semarike yehlabathi jikelele ye-anti-infective drug.
Ukongeza, i-trifluoroethanol yindawo ebalulekileyo ephakathi kwi-synthesis ye-anesthetics, ngelixa i-trifluoromethylaniline ibalulekile phakathi kwe-synthesis yamachiza e-antimalarial, i-anti-inflammatory kunye ne-analgesic drugs, i-anti-prostate drug kunye ne-anti-depressants, kwaye ithemba lemarike libanzi kakhulu. .

I-Heterocyclic intermediates.
Nge-pyridine kunye ne-piperazine njengabameli, isetyenziswa kakhulu ekuqulunqweni kweziyobisi ezichasayo, iziyobisi ezininzi zesisu, iziyobisi ezichasayo kunye ne-anti-infective, iziyobisi ezichasene ne-antihypertensive kunye neziyobisi ezitsha zomhlaza webele letrozole.

02

Amaphakathi amayeza alikhonkco elibalulekileyo kwikhonkco loshishino lwamayeza.

Umfanekiso

I-Upstream isisiseko sezinto ezisisiseko zeekhemikhali, ezininzi zazo ziyimveliso ye-petrochemical, njenge-acetylene, i-ethylene, i-propylene, i-butene kunye ne-butadiene, i-toluene kunye ne-xylene.

I-Pharmaceutical intermediates yahlulwe yaba yi-primary intermediates kunye ne-advanced intermediates.
Phakathi kwabo, ababoneleli abaphambili abaphakathi banokubonelela kuphela ngemveliso elula ephakathi kwaye baphambi kwekhonkco lezoshishino kunye noxinzelelo olukhulu lokukhuphisana kunye noxinzelelo lwexabiso. Ke ngoko, ukuguquguquka kwexabiso lezinto ezisisiseko zeekhemikhali kunempembelelo enkulu kubo.

Ngakolunye uhlangothi, ababoneleli abaphakathi abaphambili abanalo kuphela igunya eliqinileyo lokuxoxisana kubaboneleli abaphambili, kodwa okona kubaluleke ngakumbi, kuba benza imveliso yabaphakathi abaphambili kunye nomxholo ophezulu wobugcisa kunye nokugcina uqhagamshelwano olusondeleyo kunye neenkampani zamazwe ngamazwe, abachatshazelwa kancinci kukuguquguquka kwexabiso. wemathiriyeli ekrwada.

Ezona ndawo ziphakathi zezoshishino lwemichiza esulungekileyo.
Abavelisi bamayeza aphakathi amayeza badibanisa abaphakathi okanye ii-APIs ezikrwada, kwaye bathengise iimveliso ngohlobo lweemveliso zekhemikhali kwiinkampani zoxubo mayeza, ezizisulungekisayo kwaye emva koko zizithengise njengamachiza.

Amayeza aphakathi abandakanya iimveliso ezenziwe ngabenzi kunye neemveliso ezilungiselelwe wena. Ngokwezigaba ezahlukeneyo zenkonzo yokunikezela, iimodeli zoshishino ezilungiselelweyo zabaphakathi zinokuhlulwa ngokubanzi zibe yi-CRO (uphando lwekhontrakthi kunye nophuhliso lwangaphandle) kunye ne-CMO (ukukhutshwa kwemveliso yekhontrakthi).

Kwixesha elidlulileyo, imowudi yokukhutshwa kweshishini le-CMO yayisetyenziswa ikakhulu kumaziko amayeza.
Ngaphantsi kwemodeli ye-CMO, iinkampani zamachiza zikhupha imveliso kumaqabane.
Ke ngoko, ikhonkco leshishini ngokubanzi liqala ngezinto ezikhethekileyo zamayeza.
Iinkampani zoshishino kufuneka zithenge imathiriyeli ekrwada yeekhemikhali ezisisiseko kwaye zihlele kwaye zisetyenzwe ngokwemathiriyeli ekrwada yoxubo olulodwa, kwaye emva koko ziphinde ziphinde ziphinde zisebenze kwizixhobo zokuqalisa ze-API, i-cGMP intermediates, i-APIs kunye namalungiselelo.

Kodwa, njengoko iinkampani zamachiza zokulawula iindleko kunye neemfuno ezifanelekileyo, iinkonzo ezilula zokukhutshwa kwemveliso azikwazanga ukuhlangabezana nemfuno yeshishini, imo ye-CDMO (uphando lwemveliso kunye nophuhliso lwangaphandle) luvela ngexesha lembali, i-CDMO idinga amashishini okuvelisa ngokwezifiso ukuba athathe inxaxheba umthengi kwinkqubo yophando kunye nophuhliso, ukubonelela ngokuphuculwa kwenkqubo okanye ukulungiswa, ukuqonda umgangatho wemveliso enkulu, ukunciphisa iindleko zemveliso,
Inemida yengeniso ephezulu kunemodeli yeCMO.

I-downstream yi-industry yemveliso ye-API, kwaye i-API ikwi-upstream kunye ne-downstream ye-industrial chain chain relationship kunye nolungiselelo.
Ke ngoko, imfuno yokusetyenziswa kokulungiswa kweziyobisi ezantsi iya kuchaphazela ngokuthe ngqo imfuno ye-API, kwaye emva koko ichaphazele imfuno ye-intermediate.

Ngokombono walo lonke ikhonkco loshishino, abaphakathi bamayeza basekwinqanaba lokukhula ngoku, kwaye i-avareji yengeniso yenzuzo ngokubanzi i-15-20%, ngelixa i-avareji yengeniso ye-API yi-20-25%, kunye ne-avareji. ireyithi yengeniso ye-gross ye-lowstream yamalungiselelo amayeza iphezulu ukuya kuma-40-50%. Ngokucacileyo, ireyithi yengeniso epheleleyo yenxalenye esezantsi yomlambo iphezulu kakhulu kunaleyo yenxalenye ephezulu.
Ke ngoko, amashishini aphakathi amayeza anokwandisa ngakumbi ikhonkco lemveliso, ukwandisa inzuzo yemveliso kunye nokuphucula ukuzinza kweentengiso ngokuvelisa i-API kwixesha elizayo.

03

Uphuhliso oluphezulu lweshishini eliphakathi kwamayeza e-China lwaqala ngo-2000.

Ngelo xesha, iinkampani ezixuba amayeza kumazwe aphuhlileyo zanikela ingqalelo ngakumbi nangakumbi kuphando lwemveliso kunye nophuhliso kunye nophuhliso lwemarike njengokhuphiswano lwazo olungundoqo, kwaye zakhawulezisa ukudluliselwa kwamayeza aphakathi kunye nokudibanisa amachiza asebenzayo kumazwe asakhasayo aneendleko eziphantsi.
Ke ngoko, ishishini eliphakathi kwezamayeza eTshayina lizuze uphuhliso olugqwesileyo ngokuthatha eli thuba.
Emva kweminyaka engaphezu kweshumi yophuhliso oluzinzileyo, ngenkxaso yolawulo nemigaqo-nkqubo yesizwe ngokubanzi, iChina iye yaba sisiseko esibalulekileyo semveliso ephakathi kwicandelo lehlabathi labasebenzi kushishino lwamayeza.

Ukusukela ngowama-2012 ukuya kowama-2018, imveliso yoshishino lwamayeza aseTshayina inyuke ukusuka malunga nezigidi ezisi-8.1 zeetoni ezinobukhulu bemarike obumalunga ne-168.8 yeebhiliyoni zeeyuan ukuya kwi-10.12 yezigidi zeetoni ezinobukhulu bemarike ye-yuan ka-2010.7.

Umfanekiso

Ishishini laseTshayina eliphakathi kwezamayeza lizuze ukhuphiswano oluluqilima lwemarike, kwaye kwanamashishini athile emveliso aphakathi akwazile ukuvelisa abaphakathi abanesakhiwo esintsonkothileyo seemolekyuli kunye neemfuno eziphezulu zobugcisa. Inani elikhulu leemveliso ezinempembelelo sele ziqalisile ukulawula imarike yamazwe ngamazwe.

Nangona kunjalo, ngokubanzi, ishishini eliphakathi e-China lisekho kwixesha lophuhliso lokulungiswa kwesakhiwo semveliso kunye nokuphucula, kwaye inqanaba lobuchwepheshe lisephantsi.
Abaphakathi bamayeza asisiseko asezona mveliso ziphambili kushishino lwamayeza aphakathi kwamayeza, kwaye kukho amashishini ambalwa avelisa inani elikhulu labaphakathi boxubo mayeza kunye nokuxhasa iimveliso eziphakathi zamachiza amatsha anelungelo elilodwa lomenzi wechiza.

Okwangoku, iinkampani ezikhuphisana kakhulu kwisabelo se-A kushishino oluphakathi yiYaben Chemical, iLianhua Technology, iBoten, kunye neWanrun, eceba ukutyala imali eyi-630 yezigidi zeeyuan kulwakhiwo lwama-pharmaceutical intermediates kunye neeprojekthi ze-API ezinomthamo opheleleyo weetoni ezingama-3,155. /unyaka.
Baqhubeka nokuphuhlisa uluhlu lweemveliso ngophando kunye nophuhliso, ukuze bafumane iindlela ezintsha.

I-Yaben Chemical Co., Ltd. (300261): Iimveliso zethu eziphambili ziquka i-antitumor drug intermediates, i-antiepileptic drug intermediates kunye ne-antiviral intermediates.
Phakathi kwabo, i-ABAH, i-antiepileptic intermediate yeziyobisi, yafakwa ngokusemthethweni kwimveliso ngo-Oktobha 2014, kunye nomthamo weetoni ze-1,000.
Itekhnoloji ye-Enzyme fermentation yaziswa ngempumelelo kwi-cardiovascular intermediates ukwandisa ukukhuphisana kweemveliso.
Ngo-2017, inkampani yafumana i-ACL, inkampani esebenzayo yoxubo lweyeza eMalta, ikhawulezisa ukubekwa kwayo kwimarike yezonyango yamazwe ngamazwe kwaye iqhuba uguquko kunye nokuphuculwa kwesiseko sasekhaya.

I-BTG (300363) : igxininise kwi-intermediates yeziyobisi ezitsha / i-API elungiselelwe ishishini le-CMO, iimveliso eziphambili ngamayeza aphakathi kwe-anti-hepatitis C, i-anti-AIDS, i-hypolipidemia kunye ne-analgesia, kwaye ingundoqo yomthengisi we-Sofebuvir intermediates kwi-anti-hepatitis yaseGiliyadi. C ichiza.
Kwi-2016, ingeniso epheleleyo ye-anti-diabetes + i-anti-hepatitis C yamachiza aphakathi ifikelele kwi-660 yezigidi, ibalwa kwi-50% yengeniso epheleleyo.
Nangona kunjalo, ukusukela ngo-2017, ngenxa yokunyangwa ngokuthe ngcembe kwezigulana ze-hepatitis C kunye nokwehla kwezigulana, intengiso yaseGiliyadi yamachiza e-hepatitis C yaqala ukwehla. Ngaphezu koko, ngokuphelelwa kwamalungelo awodwa omenzi wechiza, amayeza amaninzi achasene ne-hepatitis C aqaliswa, kwaye ukhuphiswano lwaqhubeka luqina, olubangele ukuhla kwemiyalelo ephakathi kunye nengeniso.
Okwangoku, inkampani itshintshile ukusuka kwishishini le-CMO ukuya kwishishini le-CDMO ukwakha iqonga lenkonzo yehlabathi elikhokelayo kumashishini amayeza.

UBugcisa boManyano (002250) :
Iimveliso zamayeza aphakathi zibandakanyeka ikakhulu kumachiza e-antitumor, i-autoimmune, iziyobisi ze-antitifungal, iziyobisi zentliziyo, iziyobisi zesifo seswekile, i-antidepressants, iziyobisi ezilwa nomkhuhlane, iziyobisi ezichasene nomkhuhlane, ezifana nesiseko zonke zikwindawo zonyango zezona ndawo zidumileyo kunye neendawo ezibanzi zentengiso. , ukukhula okukhawulezayo kwiminyaka yakutshanje, izinga lokukhula elidibanisa ingeniso elimalunga nama-50%.
Phakathi kwabo, "imveliso yonyaka yeetoni ze-300 ze-Chunidine, iitoni ze-300 ze-Fluzolic Acid kunye neetoni ze-200 zeProjekthi ye-Cyclopyrimidine Acid" ifakwe kwimveliso ngokulandelelana ukususela kwi-2014.