SI21423A - Preparation of new pharmaceutically applicable forms of losartan by new methods of purification and isolation - Google Patents
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Priprava novih farmacevtsko uporabnih oblik losartana z novimi metodami čiščenja in izolacijePreparation of new pharmaceutically useful forms of losartan with new methods of purification and isolation
Področje tehnike, v katero spada izum (1PC7A61 K, A 61 K 9/19)Field of the Invention (1PC 7 A61 K, A 61 K 9/19)
Pričujoči izum spada v področje kemije heterocikličnih spojin in farmacevtske industrije ter se nanaša na nov način priprave farmacevtsko uporabnih kristaliničnih in amorfnih alkalijskih in zemijoalkalijskih soli 2-n-butil-4-kloro-5h idroksimetil-1 -[[2’-( 1 H-tetrazol-5-il)[1,1 ’-bifenil]-4-il]metil]-1 H-imidazola, znanega pod generičnim imenom losartan, in nov postopek izolacije in čiščenja teh soli za zagotovitev visoke čistoče.The present invention falls within the field of chemistry of heterocyclic compounds and the pharmaceutical industry and relates to a novel method of preparing pharmaceutically useful crystalline and amorphous alkali and earth alkali salts of 2-n-butyl-4-chloro-5h idroxymethyl-1 - [[2 '- (1H -tetrazol-5-yl) [1,1 '-biphenyl] -4-yl] methyl] -1H-imidazole, commonly known as losartan, and a new process of isolating and purifying these salts to ensure high purity.
Tehnični problemA technical problem
2-n-butil-4-kloro-5-hidroksimetil-1-[[2’-(1 H-tetrazol-5-il)[1,1 ’-bifenil]-4-il]metil]-1 Himidazol deluje na zadnjo stopnjo kaskadnega sistema renin-angiotenzin in sicer tako, da se veže na receptor za angiotenzin II. Izkoriščajoč ta biokemijski učinek se losartan v splošnem uporablja kot učinkovito antihipertenzivno sredstvo v obliki kalijeve soli (od tu naprej losartan kalij).2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1' -biphenyl] -4-yl] methyl] -1 to the last stage of the renin-angiotensin cascade system by binding to the angiotensin II receptor. Taking advantage of this biochemical effect, losartan is generally used as an effective antihypertensive agent in the form of potassium salt (henceforth losartan potassium).
Obstaja potreba po losartanu oziroma losartan kaliju visoke čistoče in po novem postopku za njegovo pripravo, po katerem bi dobili želeno snov na enostavno izvedljiv in robusten način ter z visokim dobitkom in visoko čistočo. Prav tako je zaželeno imeti učinkovino v takšni obliki, da se jo enostavno vgradi v farmacevtsko formulacijo, ki zagotovi visoko biološko razpoložljivost. Za vgradnjo v farmacevtsko obliko morajo Imeti učinkovine določene želene fizikalno-kemijske lastnosti.There is a need for losartan and / or losartan potassium of high purity and a new process for its preparation to obtain the desired substance in an easily feasible and robust manner, with high yield and high purity. It is also desirable to have the active substance in such a form that it is readily incorporated into a pharmaceutical formulation that ensures high bioavailability. For incorporation into the pharmaceutical form, the active ingredients must have certain desired physicochemical properties.
Stanje tehnikeThe state of the art
Substituirani imidazoli z delovanjem na renin-angiotenzinski sistem regulacije krvnega pritiska, med katere spada tudi losartan, so bili razkriti v patentih EP 2533310 in US 5138069.Substituted imidazoles acting on the renin-angiotensin blood pressure regulation system, including losartan, have been disclosed in patents EP 2533310 and US 5138069.
Vlagatelji patenta EP 2533310 so na splošno zaščitili različne substituirane imidazole in njihove soli, med njimi so na splošno našteli amonijeve, kalcijeve, kalijeve in natrijeve soli, specifično pa so opisali reakcije, ki vodijo do kalijevih in natrijevih soli nekaterih substituiranih imidazolov in karakterizirali njihove produkte. Presenetljivo je, da je spojina 2-/7-butil-4-kloro-5-hidroksimetil-1-[[2’-(1H-tetrazol-5il)[1 ,r-bifenil]-4-il]metil]-1 H-imidazol, ki so jo kasneje poimenovali losartan, v eksperimentalnem delu opisana le v nesolni, to je amfoterni obliki. Eksperimentalni del tega patenta tako navaja, da pri sintezi losartana iz cianobifenilnega intermediata (to je iz 2-n-butil-4-kloro-1-[(2’-cianobifenil-4-il)-metil]-5(hidroksimetil)imidazola) z natrijevim azidom izpade losartan v obliki rahlo rumenih kristalov. Patentna prijava omenja tudi, da so primerjali učinkovitost zniževanja krvnega pritiska natrijeve soli 2-n-butil-4-kloro-5-hidroksimetil-1-[[2'-(1H-tetrazol-5il)[1,1’-bifenil]-4-il]metil]-1 H-imidazola pred in po dajanju furosemida živalim, vendar spojina v patentu ali kaki drugi objavi ni karakterizirana, niti ni vnesena v register Chemical Abstracts.Applicants for EP 2533310 have generally protected various substituted imidazoles and their salts, generally listing ammonium, calcium, potassium and sodium salts, and specifically describing the reactions leading to the potassium and sodium salts of some substituted imidazoles and characterizing their products . Surprisingly, the compound is 2- [7-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5yl) [1,1'-biphenyl] -4-yl] methyl] - 1 H-imidazole, later called losartan, was described in the experimental section only in non-saline, i.e. amphoteric form. The experimental part of this patent thus states that in the synthesis of losartan from a cyanobiphenyl intermediate (i.e. from 2-n-butyl-4-chloro-1 - [(2'-cyanobiphenyl-4-yl) -methyl] -5 (hydroxymethyl) imidazole ) Losartan in the form of slightly yellow crystals is released by sodium azide. The patent application also mentions that the effectiveness of reducing the blood pressure of the sodium salt of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5yl) [1,1'-biphenyl] was compared -4-yl] methyl] -1H-imidazole before and after administration of furosemide to animals, but the compound is not characterized in the patent or any other publication or entered in the Chemical Abstracts Register.
Chemical Abstracts register med spojinami z losartanovo strukturno formulo oziroma njihovimi solmi navaja losartan v osnovni, to je amfoterni, obliki; spojini s tetrahidrofuranom in s piridinom; zmes z hidroklorotiazidom, kislinska adicijska kompleksa hidroklorid in hidrobromid, od soli pa p-toluensulfonat in kalijevo sol ter hidroklorid kalijeve soli. To nakazuje, da ostale alkalijske in zemljoalkalijske soli losartana niso bile karakterizirane in s tem tudi ne znane njihove uporabne lastnosti.The Chemical Abstracts Register lists losartan in its basic, i.e. amphoteric, form between the compounds of the losartan structural formula or their salts; tetrahydrofuran and pyridine compounds; a mixture with hydrochlorothiazide, the acid addition complexes hydrochloride and hydrobromide, and from the salts p-toluenesulfonate and potassium salt and potassium hydrochloride. This indicates that the other alkaline and alkaline earth salts of losartan have not been characterized and thus their known properties are unknown.
Za vgradnjo v farmacevtsko obliko morajo imeti farmacevtske aktivne učinkovine določene želene fizikalno-kemijske lastnosti, kot so na primer: topnost v vodi in nekaterih topilih, primerna velikost delcev, stabilnost, nehigroskopnost; ki jih lahko reguliramo z izborom prave soli, adukta, kompleksa in oblike, s tem pa dosežemo učinkovito biorazpoložljivost.For incorporation into the pharmaceutical form, the active pharmaceutical ingredients must have certain desired physicochemical properties, such as: solubility in water and certain solvents, suitable particle size, stability, non-hygroscopicity; which can be regulated by choosing the right salt, adduct, complex and form to achieve effective bioavailability.
Alkalijske ali zemljoalkalijske soli losartana je možno pripraviti zaradi kislega vodikovega atoma na tetrazolskem obroču, ki ga lahko odcepimo z dovolj močno bazo, to je s takšno, s katero dosežemo pH vodne raztopine pri ekvivalentni točki, ki je glede na US 5310928 okoli pH = 10. EP 324377 je podal postopek za tvorbo kalijeve soli losartana s kalijevim hidroksidom, nakar je bila kalijeva sol privzeta kot najprikladnejša oblika molekule za farmacevtsko uporabo.The alkali or alkaline earth salts of losartan can be prepared because of an acidic hydrogen atom on the tetrazole ring which can be cleaved with a sufficiently strong base, that is, with which the pH of the aqueous solution is reached at an equivalent point of about pH = 10 according to US 5310928. EP 324377 disclosed a process for the formation of the potassium salt of losartan with potassium hydroxide, after which the potassium salt was adopted as the most suitable form of the molecule for pharmaceutical use.
Podoben postopek priprave kristaliničnega losartan kalija podaja patentna prijava WO 02094816, kjer pa za razliko od navedenega postopka ne uporabijo vodne raztopine kalijevega hidroksida ampak dodajo trden kalijev hidroksid alkoholni raztopini losartana.A similar process for the preparation of crystalline losartan potassium is provided by patent application WO 02094816, where, unlike the said process, they do not use an aqueous solution of potassium hydroxide but add solid potassium hydroxide to an alcoholic solution of losartan.
Po postopku sinteze opisanem v patentih US 5130439 in US 5310928 preko substituiranih borovih soli nastane s hidrolizo 2-n-butil-4-kloro-5-hidroksimetil-1-[2'(2-trifen ilmetil-2H-tetrazol-5-il)[ 1,1 ’-bifen i l-4-ΐ Ijmeti I]-1 H-imidazola z žvepleno kislino v tetrahidrofuranu in kasnejšim spiranjem na koloni z dikalijevim hidrogenfosfatom ter s koncentriranjem sprane vodne raztopine ob dodatku /propanola kristaliničen losartan kalij. Ta patent omenja tudi postopek priprave losartan kalija s sušenjem z razprševanjem, vendar nikjer ne navaja, da naj bi tako dobljena substanca ne bila kristalinična.According to the synthesis procedure described in US Patents 5130439 and US 5310928, substituted boron salts are formed by hydrolysis of 2-n-butyl-4-chloro-5-hydroxymethyl-1- [2 '(2-triphenylmethyl-2H-tetrazol-5-yl) ) [1,1 '-biphen and 1-4-Ihtim I] -1 H-imidazole with sulfuric acid in tetrahydrofuran and subsequent rinsing on a dicalium hydrogen phosphate column and by concentrating the washed aqueous solution with crystalline losartan potassium in addition / propanol. This patent also mentions the process of preparing losartan potassium by spray drying, but it does not state that the substance thus obtained is not crystalline.
Iz napisanega je razvidno, da se običajno kot baza pri pretvorbi losartana v losartan kalij uporabljata kalijev hidroksid in dikalijev hidrogenfosfat. V brezvodnih pogojih je na splošno možno pripraviti soli nekaterih heterocikličnih spojin tudi z alkalijskimi ali zemljoalkalijskimi alkoholati, kar je pri nekaterih tetrazolskih spojinah glede na EP 495626 že znano, ne pa pri samem losartanu.It is clear from the foregoing that potassium hydroxide and dicalium hydrogen phosphate are commonly used as a base for the conversion of losartan to losartan potassium. Under anhydrous conditions, it is generally possible to prepare salts of some heterocyclic compounds also with alkali or alkaline earth alcohols, which is already known for some tetrazole compounds according to EP 495626 but not for losartan itself.
Ugotovljeno je bilo, da losartan kalij nastopa v dveh polimorfnih oblikah [Pharm. Res. 10 (1993), 900]. Avtorji patenta US 5608075 navajajo, da polimorfna oblika I, ki je karakterizirana z DSC endotermo pri 229.5 °C pri segrevanju prehaja v polimorfno obliko II, ki je karakterizirana z endotermnim maksimumom taljenja pri 273.2°.Losartan potassium has been found to occur in two polymorphic forms [Pharm. Really. 10 (1993), 900]. The authors of US 5608075 state that polymorphic Form I, which is characterized by a DSC endotherm at 229.5 ° C, undergoes heating upon polymorphic Form II, characterized by an endothermic maximum melting point at 273.2 °.
Iz opisa patenta US 5859258 je razvidno, da zgolj določena oblika polimorfa ne zagotavlja nujno primernih fizikalno-kemijskih lastnosti. Ugotovljeno je bilo, da lahko nekontrolirana kristalizacija privede do tvorbe velikih trodimenzionalnih skupkov, ki so neprimerni za vgradnjo v farmacevtsko obliko, v smislu izuma pa navajajo zelo strogo kontroliran proces, v katerem je presenetljivo treba izpolniti kar 14 različnih pogojev, da zagotovijo primerno obliko delcev za farmacevtsko uporabo. Potreba po tako strogo kontroliranem procesu zaradi svoje nerobustnosti lahko v pogojih industrijske proizvodnje vodi do večjega števila napak, ki lahko bistveno vplivajo na končni produkt.It is apparent from the description of US patent 5859258 that a particular form of polymorph does not necessarily provide suitable physicochemical properties. It has been found that uncontrolled crystallization can lead to the formation of large three-dimensional clusters, which are unfit for incorporation into the pharmaceutical form, and according to the invention state a very strictly controlled process in which as many as 14 different conditions are surprisingly fulfilled in order to provide a suitable particle shape for pharmaceutical use. The need for such a tightly controlled process due to its rigidity can lead to a greater number of defects in industrial production conditions, which can significantly affect the final product.
Avtorji patenta US 5128355 so pripravili in karakterizirali nekatere spojine, ki so strukturno zelo podobne losartanu. Presenetljivo je, da sta bromo in jodo analoga losartana: 2-n-butil-4-bromo-5-hidroksimetil-1-[[2'-(1 H-tetrazol-5-il)[1,T-bifenil]-4il]metil]-1 H-imidazol in 2-n-butil-5-hidroksimetil-4-jodo-1 -[[2'-( 1 H-tetrazol-5-il)[1,1 'bifenil]-4-il]metil]-1 H-imidazol amorfni substanci, medtem ko je 2-n-butil-4-kloro-5hidroksimetil-1 -[[2’-( 1 H-tetrazol-5-il)[1,1 ’-bifenil]-4-il]meti l]-1 H-imidazol (losartan) kristaliničen. Prav tako je presenetljivo, da je spojina 2-n-propil-4-kloro-5hidroksimetil-1-[[2'-(1H-tetrazol-5-il)[1,1-bifenil]-4-il]metil]-1 H-imidazol, opisana v tem patentu, ki se od losartana razlikuje ie po eni stranski verigi, amorfna.The authors of US patent 5128355 have prepared and characterized some compounds that are structurally very similar to losartan. Surprisingly, bromo and iodine are losartan analogs: 2-n-butyl-4-bromo-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1, T-biphenyl] - 4yl] methyl] -1H-imidazole and 2-n-butyl-5-hydroxymethyl-4-iodo-1 - [[2 '- (1H-tetrazol-5-yl) [1,1' biphenyl] -4 -yl] methyl] -1H-imidazole amorphous substances, while 2-n-butyl-4-chloro-5hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1' -biphenyl] -4-yl] methyl 1] -1H-imidazole (losartan) crystalline. It is also surprising that compound 2-n-propyl-4-chloro-5hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1-biphenyl] -4-yl] methyl] -1 H-imidazole described in this patent, which differs from losartan by one side chain, is amorphous.
Presenetljivo je, da po sedanjem stanju tehnike ni bilo mogoče pripraviti amorfne oblike samega losartan kalija. Losartan je v vseh pripravljenih oblikah nastopal kot kristaliničen produkt [Egypt. J. Pharm. Sci. 40, (1999), 49]. Znano je, da se v nekaterih slučajih, ko se čistih spojin ne da dobiti v amorfni obliki, doda farmacevtsko sprejemljive primesi, da se učinkovina izloči v trdno stanje brez tvorbe ponavljajoče se kristalne rešetke, kar je značilno za amorfno stanje. Tako je iz WO 0142221 znano, da so celekoksib, ki je sicer poznan v več polimorfnih oblikah, uspeli dobiti v amorfni obliki samo z dodajanjem inhibitorjev kristalizacije kot so polivinilpirolidon ali hidroksipropilmetilceluloza, dobljeni kompoziti pa so imeli zaradi amorfne narave spojine povečano biološko razpoložljivost. V patentuSurprisingly, the amorphous form of losartan potassium alone could not be prepared by the present state of the art. Losartan has been a crystalline product in all its forms [Egypt. J. Pharm. Sci. 40, (1999), 49]. It is known that in some cases where pure compounds cannot be obtained in amorphous form, pharmaceutically acceptable admixtures are added to remove the active substance into the solid state without forming a recurrent crystal lattice, which is characteristic of the amorphous state. Thus, it is known from WO 0142221 that celecoxib, which is otherwise known in several polymorphic forms, was only able to be obtained in amorphous form by the addition of crystallization inhibitors such as polyvinylpyrrolidone or hydroxypropylmethylcellulose, and the resulting composites had increased bioavailability due to the amorphous nature of the compound. In the patent
US 6284277 so opisane farmacevtske formulacije pripravljene z liofilizacijo, kjer gre za kombinacijo amorfne in kristalinične faze in v katerih so pretežno amorfne aktivne učinkovine in manitol kombinirali s pretežno kristaliničnim alaninom. Med številnimi aktivnimi učinkovinami, ki jih našteva imenovan patent, je imenovan tudi losartan, ni pa naveden v nobenem izvedbenem primeru, niti ni navedeno, če gre za kalijevo sol.US 6284277 discloses pharmaceutical formulations prepared by lyophilization, which is a combination of an amorphous and crystalline phase and in which the predominantly amorphous active ingredients and mannitol are combined with predominantly crystalline alanine. Among the many active ingredients listed by the patent name, it is also called losartan but is not mentioned in any embodiment, nor is it mentioned in the case of potassium salt.
Kristalne oblike identificiramo s fizikalno-kemijskimi metodami, ki merijo parametre, ki so odvisni od molekulske soseščine. Najbolj uporabljane metode so diferencialna termična analiza, infrardeča spektroskopija, jedrska magnetna resonanca trdnih vzorcev in rentgenska difrakcija.Crystalline forms are identified by physicochemical methods that measure molecular-dependent parameters. The most commonly used methods are differential thermal analysis, infrared spectroscopy, solid-state nuclear magnetic resonance, and x-ray diffraction.
Infrardeča spektroskopija je metoda, ki na podlagi absorbcije IR svetlobe detektira nizkoenergetske prehode predvsem na ravni vezi, ki so posledice molekulskih vibracij in nihanj. Te so predvsem odvisna od narave molekule in njenih vezi, nanje pa lahko vpliva tudi soseščina molekule. Zato je postala široko sprejeta metoda za karakterizacijo polimorfov. Ni pa vedno nujno, da se različne kristalne oblike izražajo tudi v različnih IR spektrih. Razlike se lahko kažejo v prisotnosti ali odsotnosti določenih nihanj oziroma vibracij, v ojačanih ali oslabelih trakovih in v premikih valovnih dolžin pri posameznih nihanjih oziroma vibracijah. Tudi za amorfno snov velja, da ni nujno da se IR spekter razlikuje od kristalne oblike, običajno pa gre za odsotnost nekaterih trakov, ki so funkcija medmolekulskih vezi, prisotnih zaradi urejenosti v kristalu.Infrared spectroscopy is a method that, based on the absorption of IR light, detects low-energy transitions mainly at the bond level, which are the result of molecular vibrations and vibrations. These are primarily dependent on the nature of the molecule and its bonds, and may be influenced by the neighborhood of the molecule. Therefore, it has become a widely accepted method for the characterization of polymorphs. However, it is not always necessary for different crystal forms to be expressed in different IR spectra. Differences can be manifested in the presence or absence of certain oscillations or vibrations, in amplified or weakened bands, and in the wavelength movements of individual oscillations or vibrations. Also, for an amorphous substance, the IR spectrum does not necessarily have to be distinguished from the crystalline form, but usually it is the absence of some bands that are a function of the intermolecular bonds present due to the orderliness of the crystal.
Jedrska 13C magnetna resonanca trdnih vzorcev je primerna metoda za določevanje struktur trdnih vzorcev. Tako lahko določimo posamezne polimorfne modifikacije. Na enostaven način lahko določimo solvate, na preprost način pa lahko študiramo tudi konformacijske polimorfe. Spektre z visokimi resolucijami in signale z dobrimi intenzitetami dobimo s CP/MAS (cross-polarization / magic angle spinning spectrum) tehniko snemanja [Sedon K.R. in al, Crystal Engineering: The Design and Application of Functional Solids, Kluwer Academic Publishers, 1999]. Pri merjenju dveh različnih polimorfov bi pričakovali, da bomo dobili dva enaka spektra, saj sta dva ogljika v obeh primerih povezana na enak način. Razlika pa se v resnici pokaže, ker se sicer enaki spojini nahajata v različnih kemijskih okoljih [Bugay D.E.: Magnetic Resonance Spectrometry v: Brittain H.G., Physical Characterization of Pharmaceutical Solids]. Najlaže določimo strukturo vzorcem, ki so čisti in vsebujejo le eno kristalno obliko. V primeru, da imamo zmes različnih oblik, pa dobimo kemijske premike, ki se lahko medsebojno prekrivajo in nas zavedejo pri določevanju kristalne strukture. Tako lahko napačno zaključimo, da imamo novo polimorfno modifikacijo. Spekter amorfne oblike je običajno bolj enostaven zaradi odsotnosti nekaterih informacij, ki so bile v kristalnih oblikah funkcija specifičnega okolja, v katerem se nahajajo jedra, to okolje pa je pri amorfni obliki neponavljajoče, vrhovi pa so pri amorfnih oblikah ponavadi širši. 13 C magnetic resonance of solid samples is a suitable method for determining the structures of solid samples. Individual polymorphic modifications can thus be determined. Solvates can be determined in a simple way, and conformational polymorphs can also be studied in a simple way. High resolution spectra and good intensity signals are obtained by CP / MAS (cross-polarization / magic angle spinning spectrum) recording technique [Sedon KR et al, Crystal Engineering: The Design and Application of Functional Solids, Kluwer Academic Publishers, 1999]. When measuring two different polymorphs, we would expect to get two identical spectra, since the two carbons in each case are connected in the same way. The difference, however, is indeed shown because otherwise the same compounds are found in different chemical environments [Bugay DE: Magnetic Resonance Spectrometry in: Brittain HG, Physical Characterization of Pharmaceutical Solids]. The structure is most easily determined by samples that are pure and contain only one crystalline form. If we have a mixture of different shapes, we get chemical shifts that can overlap and mislead us in determining the crystal structure. Thus, we may mistakenly conclude that we have a new polymorphic modification. The spectrum of the amorphous form is usually simpler because of the absence of some information that, in crystalline forms, was a function of the specific environment in which the nuclei are located, and this environment is non-repetitive in the amorphous form, and peaks are usually wider in amorphous forms.
Bistveno bolj natančno, kot z infrardečo spektroskopijo in NMR metodami za trdne vzorce, pri katerih spremembe detektiramo le na tistih atomih in vezeh, ki neposredno interferirajo s sosednjimi molekulami, lahko definiramo kristalno rešetko z rentgensko difrakcijo. Iz rentgenske uklonske slike dobro urejenega velikega kristala lahko natančno definiramo prostorsko sliko molekule, pri merjenju praškovnega vzorca pa lahko odkrijemo razlike med različnimi kristalnimi rešetkami, položaja posameznih atomov pa ne moremo natančno določiti. Poleg identifikacije drugačnega urejanja molekul v kristal, kar je znak za drugačno kristalno obliko, lahko iz praškovnega difraktograma dobimo tudi informacijo o stopnji urejenosti oziroma kristaliničnosti, pri čemer se slabša urejenost kaže v razširitvi trakov v difraktogramu. Skrajna oblika neurejenosti trdne snovi je amorfno stanje, ki ne kaže ponavljanja vzorca molekularne usmeritve v trdni snovi, zato pride do difuzne razpršitve rentgenske svetlobe, kar se kaže v zveznem uklanjanju v difraktogramu v celotenem merjenem območju. Z opisano metodo lahko odkrijemo, da je v snovi več različnih kristalnih oblik, lahko jim celo določimo njihovo masno razmerje. Rentgenska praškovna difrakcija je ključna metoda za razlikovanje različnih kristalnih oblik in razlikovanje amorfne od kristalne oblike tudi v primerih, ko ostale metode, na primer IR in 13C CP/MAS NMR spektroskopija, ne pokažejo nobenih razlik med vzorci.Significantly more accurate than X-ray diffraction can be defined by infrared spectroscopy and NMR methods for solid samples whose changes are detected only on those atoms and bonds that directly interfere with adjacent molecules. From the X-ray diffraction image of a well-ordered large crystal, the spatial image of the molecule can be precisely defined, and when measuring the powder sample, differences between different crystal lattices can be detected, and the position of the individual atoms cannot be determined precisely. In addition to identifying different ordering of molecules into a crystal, which is a sign of a different crystal form, information on the degree of orderliness or crystallinity can also be obtained from the powder diffractogram, with a worse orderliness reflected in the expansion of the bands in the diffractogram. The extreme form of a disordered solid is an amorphous state that does not show a repetition of the molecular orientation pattern in the solid, and therefore diffuse X-ray scattering occurs, which is reflected in the continuous removal in the diffractogram throughout the measured range. With the described method we can discover that there are several different crystalline forms in the substance, we can even determine their mass ratio. X-ray powder diffraction is a key method for distinguishing different crystalline forms and distinguishing amorphous from crystalline form even in cases where other methods, such as IR and 13 C CP / MAS NMR spectroscopy, show no differences between the samples.
Rentgenska difrakcija je, potem ko smo snov karakterizirali z različnimi analitskimi tehnikami, ključna metoda za razlikovanje amorfne od kristalne oblike, saj lahkoAfter characterization of the substance by various analytical techniques, X-ray diffraction is a key method for distinguishing amorphous from crystalline form, since
-7I snov opredelimo kot amorfno na podlagi odsotnosti odklonov pri vseh kotih v njenem rentgenskem praškovnem difraktogramu.The -7I is defined as amorphous based on the absence of deviations at all angles in its X-ray powder diffraction pattern.
Znano je, da zaradi vnosa v telo, za farmacevtske aktivne učinkovine, zahtevamo še posebno čiste snovi, da ne pride do nezaželenih in toksičnih učinkov. Substance čistimo po različnih metodah, kot so za trdne snovi, med drugim toplotne in druge prekristalizacije, preobarjanja s topili ali reagenti, ekstrakcije in spiranja, regulacije pH, kromatografske metode. Vlagatelji patenta EP 2533310 so končni produkt čistili s prekristalizacijo amfotera iz acetonitrila. Kasnejše objave kot na primer WO 9310106 in WO 9517396 navajajo bolj komplicirane in daljše postopke za zagotovitev visoke čistoče losartan kalija, ki zajemajo toplotne kristalizacije amfotera in kalijeve soli, uporabo kolonske kromatografije in uporabo adsorbcijskih nosilcev. Vlagatelji patentov EP 1106611 in US 6350880 navajajo, da so te metode nezadovoljive in predlagajo čiščenje preko soli losartana z enobaznimi kislinami kot so kloridi, bromidi in p-toluensulfonati. Vendar gre v končni fazi za enostopenjsko prekristalizacijo iz kislinske soli v alkalijsko sol s kalijevim hidroksidom, pri čemer pride do tvorbe večjih količin kalijeve soli anionskega dela soli losartana, ki se lahko koprecipitira na losartan kalij kot nečistoča, sama kristalizacija pa se vrši v acetonitrilu, ki za zadnjo stopnjo ni priporočljivo topilo zaradi toksičnosti,It is well known that, because of the introduction into the body, of pharmaceutical active ingredients, particularly pure substances are required to avoid undesirable and toxic effects. Substances are purified by various methods, such as for solids, including thermal and other recrystallization, solvent or reagent digestion, extraction and washing, pH regulation, chromatographic methods. Applicants for EP 2533310 purified the final product by recrystallizing the acetonitrile amphoter. Subsequent publications such as WO 9310106 and WO 9517396 list more complicated and lengthy processes for ensuring high purity of losartan potassium, covering thermal crystallization of amphoter and potassium salts, use of column chromatography and use of adsorption media. Applicants EP 1106611 and US 6350880 state that these methods are unsatisfactory and propose purification via losartan salts with monobasic acids such as chlorides, bromides and p-toluenesulfonates. However, ultimately, it is a one-step recrystallization from an acid salt to an alkali salt with potassium hydroxide, resulting in the formation of large amounts of the potassium salt of the anionic moiety of losartan, which can be coprecipitated onto losartan potassium as impurity, and the crystallization itself is carried out in acetonitrile, which is not a toxic solvent for the last stage,
EP 324377 opisuje farmacevtske pripravke v katerih se od 1 do 500 mg losartana dnevno kombinira z drugimi substancami, na primer diuretiki ter navaja indikacijo hipertenzijo. Patentna prijava WO 9219228 pa opisuje optimizirane sestave tablet, primerne za direktno stiskanje.EP 324377 describes pharmaceutical preparations in which 1 to 500 mg of losartan is combined daily with other substances, for example diuretics, and provides an indication of hypertension. However, patent application WO 9219228 describes optimized tablet compositions suitable for direct compression.
Opis slikDescription of the pictures
Slika 1: DSC krivulja kristalinične kalijeve soli losartanaFigure 1: DSC curve of crystalline potassium salt of losartan
Slika 2: DSC krivulja amorfne kalijeve soli losartanaFigure 2: DSC curve of the amorphous potassium salt of losartan
Slika 3: DSC krivulja kristalinične natrijeve soli losartanaFigure 3: DSC curve of crystalline sodium salt of losartan
Slika 4: DSC krivulja amorfne natrijeve soli losartanaFigure 4: DSC curve of amorphous losartan sodium salt
Slika 5: DSC krivulja magnezijeve soli losartanaFigure 5: DSC curve of the losartan magnesium salt
Slika 6: DSC krivulja kalcijeve soli losartanaFigure 6: DSC curve of the calcium salt of losartan
Slika 7: IR spekter kristalinične kalijeve soli losartanaFigure 7: IR spectrum of crystalline potassium salt of losartan
Slika 8: izsek IR spektra prikazanega na Sliki 7Figure 8: a section of the IR spectrum shown in Figure 7
Slika 9: IR spekter amorfne kalijeve soli losartanaFigure 9: IR spectrum of the amorphous potassium salt of losartan
Slika 10: izsek IR spektra prikazanega na Sliki 9Figure 10: a section of the IR spectrum shown in Figure 9
Slika 11: IR spekter kristalinične natrijeve soli losartanaFigure 11: IR spectrum of crystalline sodium salt of losartan
Slika 12: izsek IR spektra prikazanega na Sliki 11Figure 12: a section of the IR spectrum shown in Figure 11
Slika 13: IR spekter amorfne natrijeve soli losartanaFigure 13: IR spectrum of the amorphous sodium salt of losartan
Slika 14: izsek IR spektra prikazanega na Sliki 13Figure 14: a section of the IR spectrum shown in Figure 13
Slika 15: IR spekter magnezijeve soli losartanaFigure 15: IR spectrum of the losartan magnesium salt
Slika 16: IR spekter kalcijeve soli losartanaFigure 16: IR spectrum of the calcium salt of losartan
Slika 17:13C CP/MAS NMR meritev vzorca kristalinične kalijeve soli losartana Slika 18:13C CP/MAS NMR meritev vzorca amorfne kalijeve soli losartana Slika 19: rentgenski praškovni difraktogram kristalinične kalijeve soli losartana oblika IFigure 17: 13 C CP / MAS NMR measurement of losartan crystalline potassium salt sample Figure 18: 13 C CP / MAS NMR measurement of losartan amorphous potassium saline sample Figure 19: Losartan crystalline potassium X-ray powder diffraction pattern
Slika 20: rentgenski praškovni difraktogram amorfne kalijeve soli losartana Slika 21: rentgenski praškovni difraktogram kristalinične natrijeve soli losartana Slika 22: rentgenski praškovni difraktogram amorfne natrijeve soli losartana Slika 23: rentgenski praškovni difraktogram magnezijeve soli losartana Slika 24: rentgenski praškovni difraktogram kalcijeve soli losartanaFigure 20: X-ray powder diffractogram of losartan potassium amorphous potassium Figure 21: X-ray powder diffractogram of losartan crystalline sodium salt Figure 22: X-ray powder diffractogram of losartan magnesium salt Fig. 24: X-ray powder diffractogram of losartan
Opis rešitve tehničnega problema z izvedbenimi primeriDescription of solution to a technical problem with implementation examples
Predloženi izum opisuje tvorbo popolnoma amorfnih oblik alkalijskih oziroma zemljoalkalijskih soli losartana brez dodatnih farmacevtsko sprejemljivih primesi. Pri našem raziskovalnem delu smo namreč presenetljivo ugotovili, da z liofilizacijo vodne raztopine alkalijske ali zemljoalkalijske soli losartana dobimo učinkovino v obliki finega amorfnega prahu, torej do sedaj še nepoznano obliko. S to kratko in dokaj robustno metodo, brez dolgega in strogo kontroliranega procesa kristalizacije, smo enostavno dobili losartan kalij s primernimi fizikalno-kemijskimi lastnostmi za vgradnjo v farmacevtsko obliko. Amorfna oblika ima mnogokrat boljšo biološko razpoložljivost kot kristalinične oblike, kot je razvidno že omenjenih primerov za celekoksib [WO 0142221] in nekaterih drugih primerov opisanih v US 6284277. S tem, da je v končni fazi izolacije voda kot topilo, pa smo rešili tudi problem nezaželenih ostankov topil.The present invention describes the formation of completely amorphous alkaline or earth alkali salts of losartan without additional pharmaceutically acceptable admixtures. In our research work, it was surprisingly found that by lyophilization of an aqueous solution of the alkaline or alkaline earth alkali salt of losartan, the active substance is obtained in the form of a fine amorphous powder, thus a hitherto unknown form. With this short and fairly robust method, without the long and rigorously controlled crystallization process, it was easy to obtain losartan potassium with suitable physicochemical properties for incorporation into the pharmaceutical form. The amorphous form has many times better bioavailability than the crystalline forms, as seen in the cases mentioned above for celecoxib [WO 0142221] and some other examples described in US 6284277. In the end, isolation of water as a solvent also solved the problem unwanted solvent residues.
Za pripravo kakovostnih amorfnih soli za farmacevtsko uporabo rabimo amfoterni losartan visoke čistoče, saj z liofilizacijo kot metodo amortizacije snovi ne moremo dodatno očistiti. Pri pripravi kakovostnega losartana oziroma losartan kalija visoke čistoče za vstop v liofilizacijo se je presenetljivo izkazalo, da se doseže učinkovito očiščenje že s samim prehodom amfoter - alkalijska ali zemoljoalkalijska sol amfoter, ne da bi te intermediate še posebej čistili s kristalizacijo. Postopki preko konkretnih soli dajo različne obsege očiščenja, najbolj učinkovita pa sta postopka preko natrijeve in kalijeve soli, ki iz topil izpadeta kot kristalinični soli.For the preparation of high-quality amorphous salts for pharmaceutical use, high purity amphoteric losartan is used since lyophilization as a method of depreciation of the substance cannot be further purified. When preparing high-quality losartan or losartan high-purity potassium for entry into lyophilization, it was surprising that effective purification was achieved by the amphoter-alkali or alkaline-earth amphoter transition alone, without particularly purifying them by crystallization. Processes through concrete salts give different scopes, the most effective being the processes via the sodium and potassium salts, which fall out of solvents as crystalline salts.
Postopek priprave losartan kalija, ki je predmet našega izuma ima glede na znano stanje tehnike bistveno prednost, saj se je losartan kalij očiščen preko teh dveh soli izkazal za bolj čistega kot losartan kalij, ki je bil pripravljen po opisu iz WO 9310106, kateri ne dosega farmacevtske kvalitete, ni pa v tem viru navedenega nobenega postopka, ki bi ta produkt dodatno očistil. Kot je razvidno iz izvedbenih primerov, se je kot učinkovita metoda izkazalo čiščenje tako preko natrijeve soli kot preko kalijeve soli, saj smo dobili zelo čist amfoteren losartan iz katerega smo lahko pripravili čistejši losartan kalij kot po postopku opisanem v stanju tehnike. Presenetljivo je postopek preko natrijeve soli bolj robusten, saj je vpliv spremembeThe process of preparation of losartan potassium of the present invention has a significant advantage in the prior art, since losartan potassium purified through these two salts has proven to be more pure than losartan potassium prepared according to the description of WO 9310106, which does not achieve pharmaceutical grade, but there is no process listed here to further purify this product. As can be seen from the exemplary examples, purification via sodium salt and potassium salt proved to be an effective method, since very pure amphoteric losartan was obtained from which pure pure losartan potassium could be prepared as in the prior art. Surprisingly, the sodium salt process is more robust because of the impact of the change
-1010 p H na izkoristek bistveno manjši kot pri pripravi kalijeve soli, pa tudi sam izkoristek je boljši pri pripravi natrijeve soli kot pri pripravi kalijeve soli kot podaja Tabela 1.The -1010 p H yield is significantly lower than that of potassium salt preparation, and the yield itself is better in the preparation of the sodium salt than in the preparation of the potassium salt as given in Table 1.
Tabela 1: Primerjava izkoristkov in čistoč losartana očiščenega preko različnih soliTable 1: Comparison of the yields and purities of losartan purified over different salts
Ta pretvorba snov učinkovito očisti, tako da ima dobljeni amfoterni losartan nizek nivo nečistoč in je primeren ne samo za pripravo amorfne kalijeve soli za farmacevtsko uporabo, ampak tudi za pripravo kristalinične kalijeve soli za farmacevtsko uporabo, iz takšnega amfoternega losartana pa lahko pripravimo tudi ostale visoko kvalitetne alkalijske in zemljoalkalijske soli losartana.This conversion of the substance is effectively purified so that the amphoteric losartan obtained has a low impurity level and is suitable not only for the preparation of amorphous potassium salt for pharmaceutical use, but also for the preparation of crystalline potassium salt for pharmaceutical use, and other high amphoteric losartan can be prepared quality alkaline and alkaline earth salts of losartan.
V skladu s predmetom našega izuma smo iz surovega losartana pripravili kalijevo sol losartana v amorfni obliki po naslednjem postopku: losartan smo najprej očistili po postopku v naslednjih korakih: v alkoholu raztopljen losartan smo pretvorili v kalijevo ali natrijevo sol losartana, dobljeno sol izolirali v kristalni obliki, dobljeno izolirano sol raztopili v vodi ali zmesi vode in organskega topila, dobljeni raztopini dodali anorgansko kislino do pH med okoli 3,6 in okoli 3,8, dobljeno raztopino ohladili pod okoli 10° C pri čemer seje losartan oboril ali pa smo ga izkristalizirali in tako dobljen losartan nadalje digerirali z organskim topilom; nato pa smo pripravili losartan kalij v amorfni obliki, tako da smo očiščen losartan suspendirali v vodi, dobljeno suspenzijo raztopili z dodajanjem vodne raztopine kalijevega hidroksida pri temperaturi 0 do 30 °C dokler pH raztopine ni dosegel najmanj 9,3; zamrznili dobljeno raztopino in v zadnjem koraku dobljeno zamrznjeno raztopino liofilizirali.In accordance with the object of our invention, losartan potassium salt in amorphous form was prepared from crude losartan according to the following procedure: losartan was first purified by the procedure in the following steps: losartan dissolved in alcohol was converted to losartan potassium or sodium salt, the resulting salt was isolated in crystalline form , the resulting isolated salt was dissolved in water or a mixture of water and an organic solvent, the inorganic acid was added to the solution to a pH of between about 3.6 and about 3.8, the resulting solution was cooled below about 10 ° C while the losartan was precipitated or crystallized and the resulting losartan was further digested with an organic solvent; then losartan potassium was prepared in an amorphous form by suspending the purified losartan in water, dissolving the resulting suspension by adding an aqueous potassium hydroxide solution at a temperature of 0 to 30 ° C until the pH of the solution reached at least 9.3; the resulting solution was frozen and the resulting frozen solution was lyophilized in the last step.
-1111-1111
Pri postopku čiščenju losartana s prehodom amfoter - alkalijska sol oziroma zemljoalkalijska sol - amfoter gre za dva podprocesa in sicer za pripravo soli in njeno izolacijo in za nadaljnjo pripravo amfotera iz te soli.The process of purification of losartan by passage of an amphoter - alkali salt or an alkaline earth salt - amphoter involves two subprocesses, namely the preparation of the salt and its isolation and the subsequent preparation of the amphoter from this salt.
Priprava alkalijske oziroma zemljoalkalijske soli losartana in njena izolacija:Preparation of the alkali or alkaline earth salt of losartan and its isolation:
Ugotovili smo, da lahko, v skladu s prvim delom postopka, pripravimo alkalijske ali zemljoalkalijske soli losartana, če losartan raztopimo v primernem topilu, na primer v alkoholu ali zmesi alkohola in neprotičnega topila, prednostno v /-propanolu, tako da znaša koncentracija losartana okoli 170 g/l in pri temperaturi med okoli 38°C in okoli 40°C, dodajamo vodno raztopino hidroksida alkalijske ali zemljoalkalijske kovine do pH med okoli 9 in okoli 12,5, prednostno do pH okoli 10, tekom okoli 15 min do okoli 1 ure, prednostno tekom pol ure, nakar destiliramo, dokler ne odstranimo vse azeotropne zmesi.We have found that, according to the first part of the process, the alkaline or alkaline earth salts of losartan can be prepared if dissolved in a suitable solvent such as alcohol or a mixture of alcohol and a non-protic solvent, preferably in / -propanol, such that losartan concentration is around 170 g / l and at a temperature between about 38 ° C and about 40 ° C, an aqueous alkali or alkaline earth metal hydroxide solution is added to a pH of between about 9 and about 12.5, preferably to a pH of about 10, for about 15 minutes to about 1 hours, preferably for half an hour, then distill until all the azeotropic mixture is removed.
Postopek priprave zemljoalkalijskih soli losartana smo podrobneje raziskali in jih pripravili tako, da smo raztopini losartana v primernem topilu ali mešanici topil, na primer v /-propanolu, pripravljeni tako, da je znašala koncentracija losartana okoli 170 g/l, dodali brezvoden alkoholat zemljoalkalijske kovine ali hidroksid zemljoalkalijske kovine in reakcijsko zmes mešali pri povišani temperaturi med okoli 40°C in okoli 85°C, prednostno pri temperaturi refluksa.The process of preparing the alkaline earth alkaline salts was further investigated and prepared by adding anhydrous alkaline earth metal alcohol to a solution of losartan in a suitable solvent or solvent mixture, for example in / -propanol prepared so that the losartan concentration was about 170 g / l. or alkaline earth metal hydroxide and the reaction mixture was stirred at elevated temperature between about 40 ° C and about 85 ° C, preferably at reflux temperature.
V vseh primerih smo tako pripravljene alkalijske ali zemljoalkalijske soli losartana iz raztopin /-propanola oborili z nepolarnim topilom, prednostno z n-heptanom pri nizki temperaturi, prednostno pri temperaturi pod okoli 10°C ter jih izolirali po klasičnih postopkih. Rezultat takšne priprave sta kristalinični kalijeva in natrijeva sol in presenetljivo amorfni magnezijeva in kalcijeva sol. Kristalinična kalijeva sol je po sedanjem stanju tehnika znana oblika losartana in smo jo dokazali kot kristalno obliko I, medtem ko natrijeva sol še ni bila karakterizirana. Presenetljivo se je izkazalo, da so kristali losartan natrija večji in lepše oblikovani, če zmes topil, iz katerih izpadejo, vsebuje nekaj vode. Soli losartana v skladu s predmetom našega izuma lahko pripravimo tudi v obliki s vezano vodo, na kar lahko vplivamo z izbiro pogojev, na primer pH. Kristaliničen losartan natrij pripravljen pri pH okoliIn all cases, the thus prepared alkali or alkaline earth alkali salts of losartan from solutions / -propanol were precipitated with a non-polar solvent, preferably n-heptane at low temperature, preferably at a temperature below about 10 ° C and isolated by conventional methods. The result of such preparation are crystalline potassium and sodium salts and surprisingly amorphous magnesium and calcium salts. Crystalline potassium salt is a known form of losartan by the present state of the art and has been proven to be crystalline form I, while the sodium salt has not yet been characterized. Surprisingly, crystals of losartan sodium have been found to be larger and more beautifully formed if the solvent mixture from which they fall out contains some water. Losartan salts of the present invention can also be formulated in bound water, which can be influenced by the choice of conditions, such as pH. Crystalline losartan sodium prepared at a pH of about
-1212 zadrži med okoli 3,5% in okoli 4,5% vode tudi po sušenju in odpušča vodo šele nad okoli 100 °C.-1212 retains between about 3.5% and about 4.5% of water even after drying and releases water only above about 100 ° C.
Priprava magnezijeve soli z magnezijevim alkoholatom, na primer z magnezijevim etoksidom je prednostna, saj je uporaba magnezijevega hidroksida zaradi slabe topnosti in prevladujoče pretvorbe v netopni magnezijev oksid zelo nepraktična. Presenetljivo pa smo ugotovili, da boljše rezultate, tako glede izkoristka kot kvalitete, dobimo tudi z uporabo natrijevih ali kalijevih alkoholatov v nevodnih medijih, na primer v alkoholu, namesto uporabe vodne raztopine natrijevega ali kalijevega hidroksida, sam postopek pa je tudi manj zamuden, saj ne zahteva izganjanja vode z azeotropno destilacijo. Samo raztopino natrijevega in kalijevega alkoholata najlažje dobimo z raztapljanjem komercialno dostopnega natrijevega ali kalijevega f-butoksida, lahko pa tudi z dodatkom kovinskega natrija v alkohol, vendar je treba to raztopino pripraviti pred dodatkom losartana, medtem ko lahko kalijev f-butoksid dodamo kar v raztopino losartana v alkoholu. Izkoristek je pri znani metodi s hidroksidom občutljiv na pH in prisotnost vode, vpliv teh dveh faktorjev pa je pri tej metodi skoraj izničen, kar je posebej razvidno pri pripravi kalijeve soli.Preparation of magnesium salt with magnesium alcoholate, for example with magnesium ethoxide, is preferable since the use of magnesium hydroxide is very impractical due to the poor solubility and predominant conversion to insoluble magnesium oxide. Surprisingly, we have found that better results, both in terms of yield and quality, are also obtained by using sodium or potassium alcohols in non-aqueous media, such as alcohol, instead of using aqueous sodium or potassium hydroxide, and the process itself is less time consuming, since does not require expulsion of water by azeotropic distillation. Only a solution of sodium and potassium alcoholate is most readily obtained by dissolving commercially available sodium or potassium f-butoxide, but may also be added by the addition of metallic sodium to the alcohol, but this solution must be prepared before the addition of losartan, whereas potassium f-butoxide can be added directly to the solution. losartan in alcohol. In the known hydroxide method, the yield is sensitive to pH and the presence of water, and the effect of these two factors is almost nullified in this method, which is especially evident in the preparation of the potassium salt.
Najprikladnejši postopek za pripravo losartan kalija je takšen, da losartan raztopimo v primernem topilu, na primer v alkoholu, prednostno v /-propanolu, tako da znaša koncentracija okoli 370 g/l in nakar se po dodatku kalijevega tbutoksida izloča kalijeva sol losartana, z dodatkom nepolarnega topila, na primer ogljikovodika, prednostno n-heptana pa izkoristek izločanja soli iz raztopine še povečamo. Losartan kalij izoliramo z enostavnim filtriranjem in sušenjem. Analogno pripravimo po tej metodi tudi natrijevo sol losartana, le da pri tej pretvorbi uporabimo natrijev f-butoksid.The most suitable process for the preparation of losartan potassium is that dissolve losartan in a suitable solvent, for example in alcohol, preferably in / -propanol, so that the concentration is about 370 g / l and then the potassium salt of losartan is excreted after the addition of potassium tbutoxide a non-polar solvent, for example a hydrocarbon, preferably n-heptane, and the recovery of salt from the solution is further increased. Losartan potassium is isolated by simple filtration and drying. The sodium salt of losartan is also prepared analogously by this method, except that sodium f-butoxide is used in this conversion.
Priprava losartana iz njegove zemljoalkalijske ali alkalijske soliPreparation of losartan from its alkaline earth or alkali salts
V skladu s postopkom čiščenju losartana s prehodom amfoter - alkalijska sol oziroma zemljoalkalijska sol - amfoter smo nadalje izbrano sol, pripravljeno po enem od opisanih postopkov, raztopili v okoli 5 do okoli 20 kratni količini vodi,In accordance with the process of purification of losartan with the passage of amphoter-alkali salt or earth-alkali salt-amphoter, the further selected salt prepared according to one of the described procedures was dissolved in about 5 to about 20 times the amount of water,
-1313 prednostno, da je znašala koncentracija okoli 100 g/l, pri temperaturi od okoli 5°C do okoli 25°C, prednostno v intervalu med 21 °C in 25 °C, dodali organsko topilo, prednostno etilacetat, ter nakisali z anorgansko kislino, prednostno s koncentrirano anorgansko kislino, še posebej prednostno z žvepleno (VI) kislino do pH med okoli 3,6 in okoli 3,8, prednostno do pH okoli 3,7, nakar smo reakcijsko zmes ohladili na temperaturo okoli 0°C do okoli 15°C , prednostno pod 10°C in losartan izolirali po klasičnih postopkih.-1313, preferably at a concentration of about 100 g / l, at a temperature of from about 5 ° C to about 25 ° C, preferably in the interval between 21 ° C and 25 ° C, added an organic solvent, preferably ethyl acetate, and acidified with inorganic an acid, preferably with concentrated inorganic acid, especially preferably with sulfuric (VI) acid, to a pH of between about 3.6 and about 3.8, preferably to a pH of about 3.7, and then the reaction mixture is cooled to a temperature of about 0 ° C to about 15 ° C, preferably below 10 ° C and losartan was isolated by conventional methods.
Priprava amorfnih oblik alkalijskih ali zemljoalkalijskih soli losartanaPreparation of amorphous forms of alkaline or alkaline earth salts of losartan
Ugotovili smo, da sta iz zgoraj opisanih postopkov priprave soli losartana magnezijeva in kalcijeva sol amorfni, kar smo dokazali z rentgensko praškovno analizo. Na drugi strani pa se je izkazalo, da je bila tako izolirana kalijeva sol v kristalni obliki I, ki je znana iz stanja tehnike, medtem ko smo za doslej nepoznano natrijevo sol ugotovili, da je tudi kristalinična. Zato metoda kristalizacije soli losartana iz alkoholov ali zmesi alkohola in drugega organskega topila ne more biti splošna metoda za pripravo amorfnih soli.From the above-described procedures for the preparation of losartan salts, the magnesium and calcium salts were found to be amorphous, which was proved by X-ray powder analysis. On the other hand, potassium salt in crystalline form I, known from the prior art, was found to be so isolated, while the sodium salt so far unknown was found to be crystalline. Therefore, the crystallization method of losartan salts from alcohols or mixtures of alcohol and other organic solvents cannot be a general method for the preparation of amorphous salts.
Pri iskanju bolj splošne metode za pripravo amorfnih soli losartana smo ugotovili, da lahko pripravimo amorfne oblike alkalijskih ali zemljoalkalijskih soli losartana z liofilizacijo po naslednjem postopku. Losartan, ki je na primer dobljen po opisanem postopku, smo suspendirali v vodi, tako da smo dodali od okoli 5 do okoli 20 kratno maso vode, prednostno 10 kratno maso vode, ter pri temperaturi od okoli 5°C do okoli 25°C prednostno pri sobni temperaturi, dodajali vodno raztopino hidroksida alkalijske ali zemljoalkalijske kovine, prednostno pri pripravi kalijeve soli 10% vodno raztopino kalijevega hidroksida, do pH med okoli 9 in okoli 10, prednostno do pH okoli 9,3, pri čemer se je reakcijska zmes zbistrila, raztopino smo filtrirali, zamrznili ter liofilizirali, to je zamrznjeno sušili pod znižanim pritiskom med okoli 0,1 in okoli 0,01 bar.In the search for a more general method for the preparation of losartan amorphous salts, we have found that amorphous forms of the alkaline or alkaline earth alkaline salts of losartan can be prepared by lyophilization according to the following procedure. Losartan, for example obtained by the process described, was suspended in water by adding from about 5 to about 20 times the weight of water, preferably 10 times the weight of water, and at a temperature of from about 5 ° C to about 25 ° C at room temperature, an aqueous solution of an alkali metal or alkaline earth metal hydroxide was added, preferably in the preparation of the potassium salt, a 10% aqueous potassium hydroxide solution, to a pH of between about 9 and about 10, preferably to a pH of about 9.3, whereby the reaction mixture was clarified, the solution was filtered, frozen and lyophilized, i.e. freeze-dried under reduced pressure between about 0.1 and about 0.01 bar.
Če pa imamo na voljo že za farmacevtsko uporabo primerne in dovolj čiste alkalijske ali zemljoalkalijske soli losartana se da njihove amorfne oblike pripraviti z liofilizacijo njihovih zamrznjenih vodnih raztopin.However, if suitable and sufficiently pure alkaline or alkaline earth alkali salts of losartan are already available for pharmaceutical use, their amorphous forms can be prepared by lyophilization of their frozen aqueous solutions.
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Predmet predloženega izuma so tudi farmacevtski pripravki, ki vsebujejo alkalijsko ali zemljoalkalijsko sol, prednostno kalijevo sol, losartana v amorfni obliki. Farmacevtski pripravek je lahko v obliki primerni za peroralno oziroma parenteralno uporabo in je indiciran na primer za zdravljenje hipertenzije, farmacevtski pripravek, ki je predmet tega izuma je lahko tako na primer v obliki tablet, kapsul, pelet, granul in supozitorijev. Trdne farmacevtske oblike so lahko obložene, na primer z namenom povečanja peletibilnosti ali uravnavanja razpadnosti oziroma absorpcije.The present invention also relates to pharmaceutical preparations containing an alkali or alkaline earth salt, preferably a potassium salt, losartan in an amorphous form. The pharmaceutical composition may be in a form suitable for oral or parenteral use and is indicated, for example, for the treatment of hypertension, the pharmaceutical composition of the present invention may thus be in the form of tablets, capsules, pellets, granules and suppositories, for example. Solid pharmaceutical forms may be coated, for example, to increase pelletability or to regulate degradation or absorption.
V skladu s predmetom našega izuma smo pripravili filmsko obložene tablete po postopku direktne suhe zmesi. Losartan kalij smo zmešali z laktozo, mikrokristalno celulozo, škrobom in aerosilom in zmes presejali. Dodali smo magnezijev stearat in vse skupaj ponovno zmešali. Tabletirali smo jedra z maso 160 mg. Na jedra smo nanesli filmsko oblogo pripravljeno kot vodno suspenzijo vsebujočo naslednje bistvene sestavine: hidroksipropilmetilcelulozo, hidroksipropilcelulozo, polietilenglikol in titanov dioksid, ter filmsko obložene tablete polirali s smukcem. Farmacevtske pripravke, ki vsebujejo amorfne alkalijske ali zemljoalkalijske soli losartana se da pripraviti tudi z drugimi primernimi postopki, na primer po postopku suhe granulacije.In accordance with the object of our invention, film-coated tablets were prepared by the direct dry mixture process. Losartan potassium was mixed with lactose, microcrystalline cellulose, starch and aerosil and the mixture was screened. Magnesium stearate was added and mixed again. 160 mg tablets were tableted. A film coating prepared as an aqueous suspension containing the following essential ingredients was applied to the cores: hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene glycol and titanium dioxide, and the film-coated tablets were talc-coated. Pharmaceutical preparations containing the amorphous alkali or alkaline earth salts of losartan can also be prepared by other suitable methods, for example by the dry granulation process.
Experimentalni delThe experimental part
Pripravljeno amorfno obliko kalijeve soii losartana smo, primerjajoč izmerjene lastnosti z literaturno dostopnimi podatki, oziroma s karakteristikami kristalinične kalijeve soli losartana, pripravljene po patentu US 5608075 ali kot je opisano v poskusih , opisali in določili z naslednjimi fizikalno-kemijskimi metodami:The prepared amorphous form of losartan potassium salt was compared and measured using the following physicochemical methods, comparing the measured properties with the literature data, or with the crystalline potassium salt of losartan prepared according to US Pat. No. 5608075 or as described in the experiments:
- merjenje tališča- melting point measurement
- diferencialna termična kalorimetrija- differential thermal calorimetry
- NMR spektroskopija- NMR spectroscopy
- IR spektroskopija- IR spectroscopy
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- rentgenska praškovna difrakcija .- X-ray powder diffraction.
Kristalinična kalijeva sol, ki je bila pripravljena po postopkih iz izuma skozi postopek pretvorbe amfoter - kalijeva sol - amfoter je bila prepoznana kot oblika L in je bila enaka tisti, ki je bila pripravljena po patentu US 5608075. Amorfno spojino smo z omenjenimi fizikalno-kemijskimi metodami primerjali z literaturnimi navedbami za kristalne oblike [US 5608075, Pharm. Res. 10, (1993), 900], ravno tako smo jo primerjali s kristalinično kalijevo soljo losartana, pripravljeno po patentu US 5608075.The crystalline potassium salt prepared according to the methods of the invention through the process of conversion of amphoter - potassium salt - amphoter was recognized as form L and was the same as that prepared according to patent US 5608075. The amorphous compound was mentioned by said physicochemicals. by methods have been compared with the literature references for crystalline forms [US 5608075, Pharm. Really. 10, (1993), 900], and was also compared to the crystalline potassium salt of losartan prepared according to patent US 5608075.
Natrijeve, magnezijeve in kalcijeve soli, ki so glede na sedanje stanje tehnike nepoznane, smo tudi okarakterizirali z omenjenimi fizikalno-kemijskimi metodami. Ugotovili smo, da losartan natrij, ki smo ga pripravili po zgoraj navedenih postopkih, ki so podrobneje opisani v izvedbenih primerih, obstaja v kristalni in amorfni obliki, losartan kalcij in magnezij pa sta bila identificirana samo v amorfni obliki.Sodium, magnesium and calcium salts, which are unknown in the present state of the art, were also characterized by the aforementioned physicochemical methods. We have determined that losartan sodium prepared by the above procedures, which are described in more detail in the embodiments, exists in crystalline and amorphous form, and losartan calcium and magnesium were identified only in amorphous form.
1. Tališče1. Melting point
Za merjenje tališča smo uporabljali metodo vizualnega spremljanja na mikroskopu z ogrevalno mizico in metodo po Thieleju.To measure the melting point, we used the visual monitoring method on a microscope with a heating table and the Thiele method.
Izmerjeno tališče amorfnega losartan kalija se ne razlikuje bistveno od tališča kristaliničnega losartan kalija, vzorci se talijo med 265 in 275 °C, le vizualni procesi so nad 200 °C na amorfni soli bolj zvezni in bolj izraziti v smislu zlivanja in barvanja vzorca, medtem ko je pri kristaliničnem znatnejša vidna sprememba le okrog 230 °C, to pa je temperatura, ki je iz literature znana kot pretvorbeno območje v obliko II.The measured melting point of amorphous losartan potassium does not differ significantly from that of crystalline losartan potassium, the samples melting between 265 and 275 ° C, only the visual processes above 200 ° C on the amorphous salt are more continuous and more pronounced in terms of merging and coloring of the sample, while in crystallinity, a significant change of magnitude is only around 230 ° C, which is the temperature known from the literature as the Form II conversion zone.
Razlika med tališči kristaliničnega in amorfnega losartan natrija pa je bolj razpoznavna. Kristalinična oblika ima tališče 191-196 °C, amorfna pa 171-177 °C.The difference between the crystalline and amorphous melartan sodium melting points is more recognizable. The crystalline form has a melting point of 191-196 ° C and an amorphous one of 171-177 ° C.
Taljenja kalcijeve in magnezijeve soli pod 300 °C nismo zaznali.The melting of calcium and magnesium salts below 300 ° C was not detected.
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2. Diferencialna termična analiza2. Differential thermal analysis
Uporabili smo diferenčni dinamični kalorimeter Perkin Elmer Pyris 1 DSC.We used a Perkin Elmer Pyris 1 DSC differential dynamic calorimeter.
Kristaliničen losartan kalij ima prvo endotermno spremembo nad 230 °C kar bi se skladalo s temperaturo prehod oblike I v obliko II, kar je znano iz literature. Amorfna kalijeva sol tega prehoda nima, vendar so opazne bistvene spremembe že pri nižji temperaturi, tako lahko zaznamo obširnejši eksotermni prehod med 190 in 210 °C. Nad to temperaturo vzorci že precej razpadejo in so vidno spremenjeni.Crystalline losartan potassium has a first endothermic change above 230 ° C which would be consistent with the temperature of Form I to Form II transition, which is known from the literature. The amorphous potassium salt does not have this transition, but significant changes are observed even at a lower temperature, so a wider exothermic transition between 190 and 210 ° C can be detected. Above this temperature, the specimens are already decaying and visibly altered.
Kristaliničen losartan natrij ima tališče po DSC metodi pri 195 °C, kar se ujema z meritvijo na Koflerjevem mikroskopu. Vendar lahko zaznamo večjo endotermno spremembo že na območju okrog 110 °C, sklepamo pa na izgubo kristalne vode. Amorfni losartan natrij nima teh sprememb, pretvorbe nad 240 °C pa zaznamujejo razkroj vzorcev. Že nad 150 °C pa je komaj opazen zelo raztegnjen prehod, ki ga na Koflerjevem mikroskopu opazimo kot taljenju podobno vidno spremembo med 170 in 180 °C.Crystalline losartan sodium has a melting point according to the DSC method at 195 ° C, which corresponds to the measurement on a Kofler microscope. However, a major endothermic change can be detected already in the region of about 110 ° C and the loss of crystalline water is inferred. Amorphous losartan sodium does not have these changes, and conversions above 240 ° C characterize the breakdown of the samples. Already above 150 ° C, a very elongated passage is barely noticeable, which can be seen in the Kofler microscope as a melting-like visible change between 170 and 180 ° C.
DSC termogrami vzorcev losartan kalcija in losartan magnezija so pri temperaturah nad 200 °C podobni termogramom amorfnega losartan natrija, opazimo le razkroj vzorcev na približno enakem temperaturnem območju z nekoliko različnimi dinamikami toplotnih tokov.DSC thermograms of losartan calcium and losartan magnesium samples are similar to thermograms of amorphous losartan sodium at temperatures above 200 ° C; only the decomposition of the samples in approximately the same temperature range with slightly different heat flux dynamics is observed.
DSC termogrami so prikazani v Slikah 1 do 6.DSC thermograms are shown in Figures 1 to 6.
3. 13C CP/MAS NMR spektroskopija trdne snovi3. 13 C CP / MAS NMR spectroscopy of a solid
Za snemanje vzorcev po 13C-NMR spektrov s CP-MAS metodo smo uporabljali Varianov spektrometer INOVA 600 pri 150 kHz. Vzorci so bili pomerjeni s TOSSom pri vrtenju 10 kHz, pulzu (90) 4,4 μ.A Varova INOVA 600 spectrometer at 150 kHz was used to record samples from 13 C-NMR spectra using the CP-MAS method. Samples were shifted with TOSS at 10 kHz rotation, pulse (90) 4.4 μ.
Posneli smo dve obliki kalijeve soli losartana. Kristalinična kalijeva sol kaže ostre vrhove, amorfno obliko pa zaznamujejo širši signali pri čemer so nekateri izmedWe recorded two forms of losartan potassium salt. The crystalline potassium salt exhibits sharp peaks and the amorphous form is characterized by broader signals, some of which are
-1717 njih zliti s sosednim vrhom ali so odsotni. Spektra sta prikazana na Slikah 17 in 18, popis kemijskih premikov je v Tabeli 2:-1717 fused with adjacent tip or absent. The spectra are shown in Figures 17 and 18, the inventory of chemical shifts is given in Table 2:
Tabela 2: Kemijski premiki trdnih vzorcev losartan kalija posnet po NMR metodi CP/MASTable 2: Chemical shifts of solid losartan potassium samples recorded by NMR CP / MAS method
Iz tabele je razvidno, da amorfno obliko označuje odsotnost vrhov 146,6, 134,6 in 17,1 ppm ter prisotnost širokega vrha pri 47,1 ppm, pri ostalih vrhovih gre za manjše premike v obe smeri, razširitev linij in za zlitje več vrhov v skupino.The table shows that the amorphous shape is indicated by the absence of peaks 146.6, 134.6 and 17.1 ppm and the presence of a wide peak at 47.1 ppm, with the other peaks being smaller shifts in both directions, line extensions and more tops in a group.
4. IR (infrardeča) spektroskopija4. IR (infrared) spectroscopy
Uporabili smo infrardeči spektrometer »Bio-Rad FTS-60, Digilab-Division«.We used an infrared spectrometer "Bio-Rad FTS-60, Digilab-Division".
Posneti IR spektri so razvidni iz Slik 7 do 14, najizrazitejši absorbcijski maksimumi med 1510 in 700 cm’1 pa so navedeni še v naslednjem tabelaričnema zapisu, pri čemer so vrednosti za obliko II kristalne kalijeve soli prevzete iz literature [Pharm. Res. 10(1993), 900]:The recorded IR spectra are shown in Figures 7 to 14, and the most pronounced absorption maxima between 1510 and 700 cm -1 are listed in the following table, with values for Form II crystalline potassium salts taken from the literature [Pharm. Really. 10 (1993), 900]:
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Tabela 3: Značilni trakovi [cm1] v IR spektrih raznih soli losartana na območju med 1550 in 700 cm'1 Table 3: Characteristic bands [cm 1 ] in the IR spectra of various losartan salts in the range between 1550 and 700 cm ' 1
IR spektra amorfne in kristalinične kalijeve soli se bistveno razlikujeta in to bolj ali manj po celotni skali predvsem v oblikah absorbcijskih trakov in manjših zamikih vrednosti absorbcijskih maksimumov, vendar je pri amorfni kalijevi sol najbolj izrazita značilnost v IR spektru odsotnost absorbcijskih maksimumov pri 1472 ± 5, 1342 ± 5 in med 835 in 845 cm'1. Po drugi strani pa se od oblike II. amorfna oblikaThe IR spectra of the amorphous and crystalline potassium salts differ significantly, more or less along the whole scale, mainly in the forms of absorption bands and minor displacements of the values of absorption maxima, but in the amorphous potassium salt the absence of absorption maxima at 1472 ± 5 is the most prominent feature in the IR spectrum. 1342 ± 5 and between 835 and 845 cm -1 . On the other hand, since Form II. amorphous form
-1919 razlikuje po prisotnosti trakov, ki pa jih ta kristalna oblika nima, to pa so območja 954 + 5, 949 ± 5. 870-890 in 715 + 5 cm‘1.-1919 distinguishes by the presence of bands, which, however, this crystal form does not have, which are the regions 954 + 5, 949 ± 5. 870-890 and 715 + 5 cm ' 1 .
IR spekter kristaliničnega losartan natrija je bolj podoben losartan kaliju kristalne oblike L kot pa amorfnemu losartan natriju, vendar se evidentno razlikuje od kalijeve soli z odsotnostjo vrhov pri intervalih valovnih števil 995-1000 in 870-890 cm'1 ter spremembami na območju med 820 in 850 cm’1, identificiranimi s prisotnostma vrhov 839 ± 1 in 820 ± 1 cm'1. Amorfen losartan natrij se od kristaliničnega losartan natrija razlikuje po odsotnosti vrhov na območjih valovnih števil 1472 ± 5, 1342 ± 5 in med 835 in 845 cm'1.The IR spectrum of crystalline losartan sodium is more similar to crystalline L-formartan potassium than to amorphous losartan sodium, but is distinctly different from potassium salt with the absence of peaks at wavelength intervals 995-1000 and 870-890 cm ' 1 and changes in the range between 820 and 850 cm ′ 1 , identified by the presence of peaks 839 ± 1 and 820 ± 1 cm ′ 1 . Amorphous losartan sodium differs from crystalline losartan sodium in the absence of peaks in the wavelength range 1472 ± 5, 1342 ± 5 and between 835 and 845 cm -1 .
Vse amorfne oblike soli losartana, tako kalijeva, natrijeva, magnezijeva kot kalcijeva imajo enak IR spekter, razlike so znotraj napake analitike in softverske zaznave vrednosti valovnega števila vrha traku in se razlikujejo od ostalih kristaliničnih soli po odsotnosti absorbcijskih trakov na območjih valovnih števil 1472 ± 5, 1342 ± 5 in med 835 in 845 cm'1. To lahko razložimo tako, da v spektru ni nobenih specifičnih trakov, ki bi bili rezultat vpliva kationa na energetska stanja vezi, ostali trakovi pa so le rezultat znotraj molekularnih dogajanj, saj so medmolekularni vplivi zaradi neurejenega amorfnega stanja razpršeni in zato nezaznavni v IR spektru.All amorphous forms of losartan salts, both potassium, sodium, magnesium and calcium, have the same IR spectrum, the differences are within the error of the analytics and software detect the value of the wave number of the peak band and differ from the other crystalline salts in the absence of absorption bands in the 1472 ± 5 , 1342 ± 5 and between 835 and 845 cm -1 . This can be explained by the fact that there are no specific bands in the spectrum that result from the influence of the cation on the bond energy states, and the other bands are merely a result within molecular events, since intermolecular effects due to disordered amorphous state are scattered and therefore undetectable in the IR spectrum.
5. Rentgenska praškovna analiza5. X-ray powder analysis
Vzorci so bili posneti na aparaturi Philips PVV1710 z refleksijsko tehniko pri pogojih: CuKa radiacija, območje od 2° do 37° 2Θ, korak 0.04y 2Θ, integracijski čas 1 sekunda).Samples were taken on a Philips PVV1710 apparatus with the reflection technique under the following conditions: CuKa radiation, range 2 ° to 37 ° 2Θ, step 0.04y 2Θ, integration time 1 second).
Rentgenski praškovni difraktogrami losartan kalija kažejo pri amorfnem losartan kaliju odstotnost diskretnih uklonov značilnih za kristalne oblike in zvezno uklanjanje v celotnem merjenem območju, kar je nedvomno potrditev amorfnosti materiala, za razliko od kristaliničnega vzorca, ki kaže izrazite trakove pri kotih, ki so iz stanja tehnike značilni za polimorfno obliko l. Oba difraktograma sta prikazana na priloženih Slikah 19 in 20.X-ray powder diffractograms of losartan potassium show for amorphous losartan potassium the percentage of discrete defects characteristic of crystalline forms and continuous removal throughout the measured area, which is undoubtedly a confirmation of the material amorphousness, unlike the crystalline sample, which shows pronounced bands at angles from the prior art. characteristic of polymorphic form l. Both diffractograms are shown in the accompanying Figures 19 and 20.
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Rentgenski praškovni difraktogrami losartan natrija kažejo pri amorfnem losartan natriju odstotnost uklonov in nedvomno amorfnost materiala, za razliko od kristaliničnega vzorca, ki kaže ostre trakove, ki kažejo na visoko kristaliničnost. Oba difraktograma sta prikazana na priloženih Slikah 21 in 22.X-ray powder diffractograms of losartan sodium show for amorphous losartan sodium the percentage of dips and undoubtedly amorphous material, unlike the crystalline pattern showing sharp bands indicating high crystallinity. Both diffractograms are shown in the attached Figures 21 and 22.
Rentgenski praškovni difraktogrami losartan magnezija in kalcija kažejo očitno amorfno strukturo vzorcev, ne glede nato na kakšen način so bili le-ti pripravljeni. Difraktograma tipičnih vzorcev magnezijeve in kalcijeve soli sta prikazana na priloženih Slikah 23 in 24.X-ray powder diffractograms of losartan magnesium and calcium show the apparent amorphous structure of the samples, regardless of how they were prepared. The diffractograms of typical magnesium and calcium salt samples are shown in the accompanying Figures 23 and 24.
V naslednjih izvedbenih primerih, ki pojasnjujejo, vendar v ničemer ne omejujejo našega izuma, podajamo nam znane najboljše načine priprave novih farmacevtsko uporabnih oblik losartana z novimi metodami čiščenja in izolacije v skladu s predloženim izumom.In the following embodiments, which explain, but do not limit in any way, our invention, we give us the best known methods of preparing new pharmaceutically useful forms of losartan with new methods of purification and isolation in accordance with the present invention.
Poskus 1Experiment 1
Losartan surovi (2-/?-butil-4-kloro-5-hidroksimetil-1-[[2’-(1 H-tetrazol-5-il)-bifenil-4-il] metil]-1H-imidazol)Losartan crude (2 - / - butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] methyl] -1H-imidazole)
Zmes 129,80 g 5-[2-(4-bromometilbifenilil)]-2-trifenilmetil-2H-tetrazola, 43,4 g 2-nbutil-4-kloro-5-hidroksimetil-1 H-imidazola in 38,27 g kalijevega karbonata v 550 ml Ν,Ν-dimetilacetamida mešamo prt temperaturi 0 - 5 °C 8 ur ter pri sobni temperaturi preko noči. Zmesi dodamo 8,02 g NaBH4 in 18 ml vode. Hladimo na sobno temperaturo in mešamo 3 ure. Reakcijsko zmes zlijemo med intenzivnim mešanjem v 1,1 I vode, filtriramo in oborino speremo z 550 ml vode. Vakuumsko sušimo čez noč pri sobni temperaturi nad silikagelom.A mixture of 129.80 g of 5- [2- (4-bromomethylbiphenyl)] -2-triphenylmethyl-2H-tetrazole, 43.4 g of 2-butyl-4-chloro-5-hydroxymethyl-1 H-imidazole and 38.27 g of potassium carbonate in 550 ml of Ν, Ν-dimethylacetamide was stirred at 0-5 ° C for 8 hours and at room temperature overnight. To the mixture was added 8.02 g NaBH 4 and 18 ml water. Cool to room temperature and stir for 3 hours. The reaction mixture was poured under vigorous stirring into 1.1 I of water, filtered and the precipitate was washed with 550 ml of water. Vacuum was dried overnight at room temperature over silica gel.
Dobimo 2-n-butil-4-kloro-5-hidroksimetil-1-[[2,-(trifenilmetil-2H-tetrazol-5-il) [1,1’bifenil-4-il] metiljimidazol, ki ga prekristaliziramo iz klorobutana in etilacetata s končnim dobitkom reakcije in čiščenja po sušenju 66,77 g.2-n-Butyl-4-chloro-5-hydroxymethyl-1 - [[2 , - (triphenylmethyl-2H-tetrazol-5-yl) [1,1'biphenyl-4-yl] methylimidazole is obtained which is recrystallized from of chlorobutane and ethyl acetate with a final reaction and purification yield after drying 66.77 g.
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Raztopini 67,77 g 2-n-butil-4-kloro-5-hidroksimetil-1-[[2-(trifenilmetil-2H-tetrazol-5il)[1,Tbifenil-4-il]metil]imidazola v 316 mi tetrahidrofurana (THF) dodamo med mešanjem 105,9 g 12 % HCI pri temperaturi 23°C tekom ene ure. Zmes mešamo pri sobni temperaturi čez noč. Dodajamo 30% NaOH pri temperaturi do 22°C tekom ene ure, dokler ne dosežemo pH 12,5 (cca 100 ml). Uparimo THF pri temperaturi do 60°C ter dodamo demineralizirano vodo do prvotnega volumna. Izpadlo oborino odftltiramo, speremo z 2 x 50 ml demineralizirane vode in zavržemo. Vodno fazo ekstrahiramo z 1 x 50 ml toluena. Organsko plast ločimo in vodni fazi dodamo 124 ml etilacetata. Reakcijsko zmes med intenzivnim mešanjem nakisamo s koncentrirano H2SO4 pri temperaturi 21-25°C do pH 3,63,8. Ohladimo pod 10°C in mešamo 1 uro. Izpadlo oborino filtriramo, digeriramo s 130 ml etilacetata, ponovno filtriramo in vakuumsko sušimo pri temperaturi 50°C čez noč, pri čemer dobimo 40,8 g losartana v amfoterni obliki.A solution of 67.77 g of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2- (triphenylmethyl-2H-tetrazol-5yl) [1,2-biphenyl-4-yl] methyl] imidazole in 316 m tetrahydrofuran (THF) was added while stirring 105.9 g of 12% HCl at 23 ° C for one hour. The mixture was stirred at room temperature overnight. 30% NaOH was added at a temperature of up to 22 ° C for one hour until a pH of 12.5 (approx. 100 ml) was reached. Evaporate THF at 60 ° C and add demineralized water to its original volume. The precipitated precipitate was filtered off, washed with 2 x 50 ml of demineralized water and discarded. The aqueous phase is extracted with 1 x 50 ml of toluene. The organic layer was separated and 124 ml of ethyl acetate were added to the aqueous phase. The mixture is acidified with concentrated H2SO4 at a temperature of 21-25 ° C to pH 3.63.8 during vigorous stirring. Cool below 10 ° C and stir for 1 hour. The resulting precipitate was filtered off, digested with 130 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 40.8 g of losartan in amphoteric form.
Poskus 2Experiment 2
Tvorba natrijeve soli losartana - metoda 1Losartan sodium salt formation - method 1
K 40,81 g losartana iz Poskusa 1 v 235 ml /-propanola dodajamo raztopino 5,5 g natrijevega hidroksida v 5,7 ml vode pri temperaturi 38 - 40° C do pH 12 tekom pol ure. Oddestiliramo približno 35 ml azeotropne zmesi /-propanol / voda. Dodamo 140 ml n-heptana in mešamo pri sobni temperaturi dokler ne izpade beta oborina. Redčimo s 55 ml n-heptana, filtriramo, izpiramo s 110 ml n-heptana in sušimo v vakuumu pri 50°C, pri čemer dobimo 35,0 g natrijeve soli losartana.A solution of 5.5 g of sodium hydroxide in 5.7 ml of water was added to 40.81 g of losartan from Experiment 1 in 235 ml / -propanol at a temperature of 38-40 ° C to pH 12 for half an hour. Distill off about 35 ml of azeotropic / propanol / water mixture. Add 140 ml of n-heptane and stir at room temperature until the beta precipitate disappears. It is diluted with 55 ml of n-heptane, filtered, washed with 110 ml of n-heptane and dried in vacuo at 50 ° C to give 35.0 g of the losartan sodium salt.
Tališče: 191-196 °CMelting point: 191-196 ° C
Voda po Karl-Fisherju: 4,2 %.Karl-Fisher water: 4.2%.
Vsebnost natrija 4,4 % (5,0 % na suho snov)Sodium content 4.4% (5.0% on dry matter)
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Poskus 3Experiment 3
Tvorba natrijeve soli losartana - metoda 2Losartan sodium salt formation - method 2
K 40,81 g losartana iz Poskusa 1 v 235 ml /-propanola dodajamo raztopino 5,5 g natrijevega hidroksida v 5,7 ml vode pri temperaturi 38 - 40° C do pH 10 tekom pol ure. Oddestiliramo približno 35 ml azeotropne zmesi /-propanol / voda. Dodamo 140 ml n-heptana in mešamo pri sobni temperaturi dokler ne izpade bela oborina. Redčimo s 55 ml n-heptana, filtriramo, izpiramo s 110 ml n-heptana in sušimo v vakuumu pri 50°C, pri čemer dobimo 37,0 g natrijeve soli losartana.To a solution of 40.81 g of losartan from Experiment 1 in 235 ml / -propanol was added a solution of 5.5 g of sodium hydroxide in 5.7 ml of water at a temperature of 38-40 ° C to pH 10 for half an hour. Distill off about 35 ml of azeotropic / propanol / water mixture. Add 140 ml of n-heptane and stir at room temperature until a white precipitate disappears. Dilute with 55 ml of n-heptane, filter, wash with 110 ml of n-heptane and dry under vacuum at 50 ° C to give 37.0 g of the losartan sodium salt.
Tališče: 190-198 °C Voda po Karl-Fisherju: 0,3 %.Melting point: 190-198 ° C Karl-Fisher water: 0.3%.
Poskus 4Experiment 4
Tvorba natrijeve soli losartana - metoda 3Losartan sodium salt formation - method 3
K 40,81 g losartana iz Poskusa 1 v 120 ml /-propanola dodamo 9,28 g natrijevega f-butoksida. Reakcijska zmes se zbistri. Dodamo 145 ml n-heptana ter mešamo pri sobni temperaturi dokler ne izpade bela oborina. Filtriramo in izpiramo s 165 ml nheptana. Sušimo pri 40°C v vakuumu, pri čemer dobimo 37,0 g natrijeve soli losartana.To 40.81 g of losartan from Experiment 1 in 120 ml / -propanol was added 9.28 g of sodium f-butoxide. The reaction mixture was clarified. 145 ml of n-heptane was added and stirred at room temperature until a white precipitate disappeared. Filter and wash with 165 ml of nheptane. It is dried at 40 ° C in vacuo to give 37.0 g of the losartan sodium salt.
Tališče: 191-196 °CMelting point: 191-196 ° C
Vsebnost natrija 4,7 % (5,2 % na suho snov)Sodium content of 4.7% (5.2% on dry matter)
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Poskus 5Experiment 5
Tvorba kalijeve soli losartana - metoda 1Losartan potassium salt formation - method 1
K 40,81 g losartana iz Poskusa 1 v 235 ml /-propanola dodajamo raztopino 5,5 g kalijevega hidroksida v 5,7 ml vode pri temperaturi 38-40°C do pH 12 tekom pol ure. Oddestiliramo približno 35 ml azeotropne zmesi /-propanol / voda. Dodamo 141,5 mi n-heptana in mešamo pri sobni temperaturi dokler ne izpade bela oborina. Redčimo z 54 ml n-heptana, filtriramo, izpiramo z 108 ml n-heptana in sušimo v vakuumu pri 50°C, pri čemer dobimo 21,36 g losartan kalija.A solution of 5.5 g of potassium hydroxide in 5.7 ml of water at a temperature of 38-40 ° C to pH 12 for half an hour is added to 40.81 g of losartan from Experiment 1 in 235 ml / -propanol. Distill off about 35 ml of azeotropic / propanol / water mixture. 141.5 mi of n-heptane was added and stirred at room temperature until a white precipitate disappeared. It is diluted with 54 ml of n-heptane, filtered, washed with 108 ml of n-heptane and dried in vacuo at 50 ° C to give 21.36 g of losartan potassium.
Poskus 6Experiment 6
Tvorba kalijeve soli losartana - metoda 2Losartan potassium salt formation - method 2
K 10,2 g losartana iz Poskusa 1 raztopljenega v 59 ml i-propanola dodajamo raztopino 1,4 g kalijevega hidroksida v 1,5 ml vode pri temperaturi 38-40°C do pH 10 tekom pol ure. Oddestiliramo priblilžno 19 ml azeotropne zmesi /propanol/voda. Dodamo 36 ml n-heptana in mešamo pri sobni temperaturi dokler ne izpade bela oborina. Redčimo z 14 ml n-heptana, filtriramo, izpiramo z 26 ml nheptana in sušimo v vakuumu pri 50°C, pri čemer dobimo 8,57 g losartan kalija.To a solution of 10.2 g of losartan from Experiment 1 dissolved in 59 ml of i-propanol was added a solution of 1.4 g of potassium hydroxide in 1.5 ml of water at a temperature of 38-40 ° C to pH 10 for half an hour. Distill off about 19 ml of azeotropic / propanol / water mixture. 36 ml of n-heptane was added and stirred at room temperature until a white precipitate disappeared. It is diluted with 14 ml of n-heptane, filtered, washed with 26 ml of nheptane and dried in vacuo at 50 ° C to give 8.57 g of losartan potassium.
Poskus 7Experiment 7
Tvorba kalijeve soli losartana - metoda 3Losartan potassium salt formation - method 3
K 40,81 g losartana iz Poskusa 1 v 110 ml /-propanola dodamo 10,86 g kalijevega f-butoksida pri temperaturi med 10°C in 25°C. Reakcijska zmes se zbistri, nakar izpade gosta, bela oborina. Dodamo 150 ml n-heptana ter mešamo pri sobni temperaturi 1 uro. Filtriramo in izpiramo s 75 ml n-heptana. Vakuumsko sušimo pri temperaturi 50°C čez noč, pri čemer dobimo 43,25 g losartan kalijaTo 40.81 g of losartan from Experiment 1 in 110 ml / -propanol was added 10.86 g of potassium f-butoxide at a temperature between 10 ° C and 25 ° C. The reaction mixture was clarified and a white precipitate was dropped. Add 150 ml of n-heptane and stir at room temperature for 1 hour. Filter and wash with 75 ml of n-heptane. Vacuum was dried at 50 ° C overnight to give 43.25 g of losartan potassium
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Poskus 8Experiment 8
Tvorba magnezijeve soli losartanaMagnesium salt formation of losartan
K 40,81 g losartana iz Poskusa 1 v 235 ml /-propanoia dodamo 6,07 g magnezijevega etoksida in mešamo pri temperaturi refluksa preko noči. Vroče filtriramo, dodamo 650 ml n-heptana in hladimo na sobno temperaturo, da se izobori produkt. Filtriramo in spiramo s 110 ml n-heptana. Sušimo v vakuumu pri 50°C, pri čemer dobimo 37,9 g magnezijeve soli losartana.6.07 g of magnesium ethoxide are added to 40.81 g of losartan from Experiment 1 in 235 ml / -propanoia and stirred at reflux overnight. Hot filtered, 650 ml of n-heptane was added and cooled to room temperature to precipitate the product. Filter and wash with 110 ml of n-heptane. The mixture was dried in vacuo at 50 ° C to give 37.9 g of the losartan magnesium salt.
Tališče: nad 300 °CMelting point: above 300 ° C
Vsebnost magnezija 2,9 % (3,2 % na suho snov).Magnesium content 2.9% (3.2% on dry matter).
Poskus 9Experiment 9
Tvorba kalcijeve soli losartanaCalcium salt formation of losartan
K 40,81 losartana iz Poskusa 1 v 235 ml /-propanoia dodamo 3,92 g kalcijevega hidroksida. Mešamo pri temperaturi refluksa 1 uro in vroče filtriramo. Filtratu dodamo 410 ml n-heptana in ohladimo na sobno temperaturo. Topilo oddekantiramo od smolnatega preostanka in dodamo 820 ml n-heptana. Mešamo pri 10°C dokler ne izkristalizira bela oborina. Filtriramo, izpiramo z 110 ml nheptana ter sušimo v vakuumu pri 50°C, pri čemer dobimo 39,2 g kalcijeve soli losartana.3.92 g of calcium hydroxide was added to 40.81 losartan from Experiment 1 in 235 ml / -propanoia. The mixture was stirred at reflux for 1 hour and filtered hot. 410 ml of n-heptane was added to the filtrate and cooled to room temperature. Decant the solvent from the resinous residue and add 820 ml of n-heptane. Stir at 10 ° C until a white precipitate crystallizes. It was filtered, washed with 110 ml of nheptane and dried in vacuo at 50 ° C to give 39.2 g of the calcium salt of losartan.
Tališče: nad 300°C.Melting point: above 300 ° C.
Vsebnost kalcija 4,0 % (4,7 % na suho snov).Calcium content 4.0% (4.7% on dry matter).
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Poskus 10Experiment 10
Losartan čiščen - metoda 1 g natrijeve soli losartana raztapljamo v 350 ml vode, dodamo 106 ml etilacetata in nakisamo pri temperaturi 21-25°C do pH 3,6-3,8 s koncentrirano žveplovo kislino. Ohladimo pod 10° in mešamo 1 uro. Izpadlo oborino filtriramo, digeriramo s 120 ml etilacetata, ponovno filtriramo in vakuumsko sušimo pri temperaturi 50°C preko noči, pri čemer dobimo 29,3 g losartana.Losartan purified - Dissolve 1 g of losartan sodium salt in 350 ml of water, add 106 ml of ethyl acetate and acidify at a temperature of 21-25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° and stir for 1 hour. The resulting precipitate was filtered off, digested with 120 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 29.3 g of losartan.
Poskus 11Experiment 11
Losartan čiščen - metoda 2Losartan purified - Method 2
42,66 g kalijeve soli losartana raztopimo v 430 ml vode, dodamo 130 ml etilacetata in nakisamo pri temperaturi 21°C-25°C do pH 3,6-3,8 s koncentrirano žveplovo kislino. Ohladimo pod 10°C in mešamo 1 uro. Izpadlo oborino filtriramo, digeriramo s 145 ml etilacetata, ponovno filtriramo in vakuumsko sušimo pri temperaturi 50°C preko noči, da dobimo 36,6 g losartana.Dissolve 42.66 g of the losartan potassium salt in 430 ml of water, add 130 ml of ethyl acetate and acidify at 21 ° C-25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The resulting precipitate was filtered off, digested with 145 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 36.6 g of losartan.
Poskus 12Experiment 12
Losartan čiščen - metoda 3Losartan purified - Method 3
37,9 g magnezijeve soli losartana topimo v 388 ml demineralizirane vode, dodamo 120 ml etilacetata in nakisamo pri temperaturi 21°-25°C do pH 3,6-3,8 s koncentrirano žveplovo kislino. Ohladimo pod 10°C in mešamo 1 uro. Izpadlo oborino filtriramo, digeriramo s 130 ml etilacetata, ponovno filtriramo in vakuumsko sušimo pri temperaturi 50°C preko noči, da dobimo 32,3 g losartana.Dissolve 37.9 g of the losartan magnesium salt in 388 ml of demineralized water, add 120 ml of ethyl acetate and acidify at a temperature of 21 ° -25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The precipitate which was formed was filtered off, digested with 130 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 32.3 g of losartan.
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Poskus 13Experiment 13
Losartan čiščen - metoda 4Losartan purified - Method 4
38,0 g kalcijeve soli losartana topimo v 380 ml vode, dodamo 115 ml etilacetata in nakisamo pri temperaturi 21 °- 25°C do pH 3,6-3,8 s koncentrirano žveplovo kislino. Ohladimo pod 10°C in mešamo 1 uro. Izpadlo oborino filtriramo, digeriramo s 130 ml etilacetata, ponovno filtriramo in vakuumsko sušimo pri temperaturi 50°C preko noči, da dobimo 36,2 g losartana.38.0 g of the calcium salt of losartan are dissolved in 380 ml of water, 115 ml of ethyl acetate are added and acidified at a temperature of 21 ° - 25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The resulting precipitate was filtered off, digested with 130 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 36.2 g of losartan.
Poskus 14Experiment 14
Priprava farmacevtsko uporabnega losartan kalija preko kristalnega losartan natrijaPreparation of pharmaceutically useful losartan potassium via crystalline losartan sodium
K 20,4 g surovega losartana (kromatografska čistost 98,73 %) v 120 ml /-propanola dodajamo raztopino 2,75 g natrijevega hidroksida v 2,9 ml vode pri temperaturi 38-40°C do pH 10 tekom pol ure. Oddestiliramo približno 18 ml azeotropne zmesi /-propanol / voda. Dodamo 70 ml n-heptana in mešamo pri sobni temperaturi dokler ne izpade bela oborina. Redčimo z 28 ml n-heptana, filtriramo, izpiramo s 55 ml n-heptana in sušimo v vakuumu pri 50°C, pri čemer dobimo 18.5 g kristalinične natrijeve soli losartana (izkoristek 87 %, kromatografska čistost 99,42 %).A solution of 2.75 g of sodium hydroxide in 2.9 ml of water was added to 20.4 g of crude losartan (chromatographic purity 98.73%) in 120 ml / -propanol at a temperature of 38-40 ° C to pH 10 for half an hour. Distill off about 18 ml of azeotropic / propanol / water mixture. Add 70 ml of n-heptane and stir at room temperature until a white precipitate disappears. Diluted with 28 ml of n-heptane, filtered, washed with 55 ml of n-heptane and dried in vacuo at 50 ° C to give 18.5 g of crystalline losartan sodium salt (yield 87%, chromatographic purity 99.42%).
Dobljeno substanco raztapljamo v 185 ml vode, dodamo 56 ml etilacetata in nakisamo pri temperaturi 21-25°C do pH 3,6-3,8 s koncentrirano žveplovo kislino. Ohladimo pod 10° in mešamo 1 uro. Izpadlo oborino filtriramo, digeriramo s 64 ml etilacetata, ponovno filtriramo in vakuumsko sušimo pri temperaturi 50°C preko noči, pri čemer dobimo 16,5 g losartana (izkoristek faze 94 %, kromatografska čistost 99,74 %).The resulting substance was dissolved in 185 ml of water, 56 ml of ethyl acetate was added and acidified at a temperature of 21-25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° and stir for 1 hour. The precipitate which was formed was filtered off, digested with 64 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 16.5 g of losartan (phase efficiency 94%, chromatographic purity 99.74%).
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Dobljeni produkt raztopimo v 45 ml /-propanola dodamo 4,39 g kalijevega tbutoksida pri temperaturi med 10°C in 25°C. Reakcijska zmes se zbistri, nakar izpade gosta, bela oborina. Dodamo 60 ml n-heptana ter mešamo pri sobni temperaturi 1 uro. Filtriramo in izpiramo z 30 ml n-heptana. Vakuumsko sušimo pri temperaturi 50°C čez noč, pri čemer dobimo 16,9 g losartan kalija (izkoristek faze je 94 %, kromatografska čistost 99,91%, celokupen izkoristek je 77%).The resulting product was dissolved in 45 ml / -propanol and 4.39 g of potassium tbutoxide was added at a temperature between 10 ° C and 25 ° C. The reaction mixture was clarified and a white precipitate was dropped. 60 ml of n-heptane are added and stirred at room temperature for 1 hour. Filter and wash with 30 ml of n-heptane. Vacuum was dried at 50 ° C overnight to give 16.9 g of losartan potassium (phase yield 94%, chromatographic purity 99.91%, total yield 77%).
Poskus 15Experiment 15
Priprava farmacevtsko uporabnega losartan kalija preko kristalnega losartan kalijaPreparation of pharmaceutically useful losartan potassium via crystalline losartan potassium
Kot je že opisano v poskusu 4 k 10,2 g losartana iz Poskusa 1 (kromatografska čistost 98,73 %) v 59 ml ΐ-propanola dodajamo raztopino 1,4 g kalijevega hidroksida v 1,5 ml vode pri temperaturi 38-40°C do pH 10 tekom pol ure. Oddestiliramo priblilžno 19 ml azeotropne zmesi /-propanol / voda. Dodamo 36 ml n-heptana in mešamo pri sobni temperaturi dokler ne izpade bela oborina. Redčimo z 14 ml n-heptana, filtriramo, izpiramo z 26 ml n-heptana in sušimo v vakuumu pri 50°C, pri čemer dobimo 8,57 g losartan kalija, (izkoristek: 77 %, kromatografska čistost 99,67%).As described in Experiment 4, a solution of 1.4 g of potassium hydroxide in 1.5 ml of water at a temperature of 38-40 ° is added to 4 to 10.2 g of losartan from Experiment 1 (chromatographic purity 98.73%) in 59 ml of ΐ-propanol. C to pH 10 for half an hour. Distill off about 19 ml of azeotropic / propanol / water mixture. 36 ml of n-heptane was added and stirred at room temperature until a white precipitate disappeared. It is diluted with 14 ml of n-heptane, filtered, washed with 26 ml of n-heptane and dried in vacuo at 50 ° C to give 8.57 g of losartan potassium, (yield: 77%, chromatographic purity 99.67%).
Dobljeno kalijevo sol losartana raztopimo v 86 ml vode, dodamo 26 ml etilacetata in nakisamo pri temperaturi 21°-25°C do pH 3,6-3,8 s koncentrirano žveplovo kislino. Ohladimo pod 10°C in mešamo 1 uro. Izpadlo oborino filtriramo, digeriramo s 29 ml etilacetata, ponovno filtriramo in vakuumsko sušimo pri temperaturi 50°C preko noči, da dobimo 7,35 g losartana (izkoristek faze 93%, kromatografska čistost 99,82%).The resulting losartan potassium salt was dissolved in 86 ml of water, 26 ml of ethyl acetate were added and acidified at 21 ° -25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The resulting precipitate was filtered off, digested with 29 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 7.35 g of losartan (93% yield, chromatographic purity 99.82%).
Dobljeni produkt raztopimo v 20 ml /-propanola dodamo 1,96 g kalijevega tbutoksida pri temperaturi med 10°C in 25°C. Reakcijska zmes se zbistri, nakar izpade gosta, bela oborina. Dodamo 27 ml n-heptana ter mešamo pri sobni temperaturi 1 uro. Filtriramo in izpiramo z 13 ml n-heptana. Vakuumsko sušimo priThe resulting product was dissolved in 20 ml / -propanol and 1.96 g of potassium tbutoxide was added at a temperature between 10 ° C and 25 ° C. The reaction mixture was clarified and a white precipitate was dropped. 27 ml of n-heptane are added and stirred at room temperature for 1 hour. Filter and wash with 13 ml of n-heptane. Vacuum drying at
-2828 temperaturi 50°C čez noč, pri čemer dobimo 7,66 g losartan kalija (izkoristek faze je 96 %, kromatografska čistost 99,88%, celokupen izkoristek je 69%).-2828 at 50 ° C overnight, yielding 7.66 g of losartan potassium (phase yield 96%, chromatographic purity 99.88%, overall yield 69%).
Poskus 16Experiment 16
Primerjalni poskus priprave kalijeve soli po znanem stanju tehnikeComparative attempt to prepare potassium salt according to the prior art
K 40,81 g losartana (kromatografska čistost 98,73%) v 153 ml i-propanola dodajamo zmes 10 g kalijevega hidroksida, 5,1 ml vode in 100 ml /-propanola pri temperaturi 38-40°C do pH 10-11 tekom pol ure. Oddestiliramo približno 140 ml topila (zmes /-propanol / voda) in dodamo 92 ml n-heptana. Mešamo pri sobni temperaturi dokler ne izpade bela oborina. Redčimo z 54 ml n-heptana, filtiramo, izpiramo z 70 ml n-heptana in sušimo v vakuumu pri 50°C, pri čemer dobimo 38,4 g losartan kalija (izkoristek: 86 %, kromatografska čistost: 99,67%).To 40.81 g of losartan (chromatographic purity 98.73%) in 153 ml of i-propanol was added a mixture of 10 g of potassium hydroxide, 5.1 ml of water and 100 ml / -propanol at a temperature of 38-40 ° C to pH 10-11 for half an hour. Distill off about 140 ml of solvent (mixture / propanol / water) and add 92 ml of n-heptane. Stir at room temperature until a white precipitate disappears. It is diluted with 54 ml of n-heptane, filtered, washed with 70 ml of n-heptane and dried in vacuo at 50 ° C to give 38.4 g of losartan potassium (yield: 86%, chromatographic purity: 99.67%).
Poskus 17Experiment 17
Amorfna kalijeva sol losartana - metoda 1Losartan amorphous potassium salt - method 1
29,3 g čiščenega losartana iz enega od poskusov 8 do 11 suspendiramo v 293 ml vode. Pri sobni temperaturi naravnamo pH na 9,3 z 10% vodno raztopino kalijevega hidroksida. Reakcijska zmes se zbistri. Raztopino filtriramo in liofiliziramo. Dobimo bel, popolnoma amorfen produkt losartan kalij v količini 31,8 g29.3 g of purified losartan from one of experiments 8 to 11 were suspended in 293 ml of water. At room temperature, the pH was adjusted to 9.3 with 10% aqueous potassium hydroxide solution. The reaction mixture was clarified. The solution was filtered and lyophilized. A white, completely amorphous product of losartan potassium is obtained in an amount of 31.8 g
Poskus 18Experiment 18
Amorfna kalijeva sol losartana - metoda 2Losartan amorphous potassium salt - method 2
20,0 g kristalne kalijeve soli losartana topimo v 200 ml destilirane vode. Bistro raztopino filtriramo in liofiliziramo. Dobimo amorfno kalijevo sol losartana v količini 20,0 g.20.0 g of the crystalline potassium salt of losartan are dissolved in 200 ml of distilled water. The clear solution was filtered and lyophilized. The amorphous potassium salt of losartan is obtained in an amount of 20.0 g.
-2929-2929
Poskus 19Experiment 19
Amorfna natrijeva sol losartana - metoda 1Losartan amorphous sodium salt - method 1
5,0 g čiščenega losartana iz enega poskusa 8 suspendiramo v 50 ml vode. Pri sobni temperaturi naravnamo pH na 9,62 z 10% vodno raztopino natrijevega hidroksida. Reakcijska zmes se zbistri. Raztopino filtriramo in liofiliziramo. Dobimo amorfno natrijevo sol losartana v količini 5,2 g.Suspend 5.0 g of purified losartan from Experiment 8 in 50 ml of water. At room temperature, the pH was adjusted to 9.62 with 10% aqueous sodium hydroxide solution. The reaction mixture was clarified. The solution was filtered and lyophilized. The amorphous sodium salt of losartan is obtained in an amount of 5.2 g.
Poskus 20Experiment 20
Amorfna natrijeva sol losartana - metoda 2Losartan amorphous sodium salt - method 2
3,10 g kristalne natrijeve soli losartana topimo v 31 ml vode. Bistro raztopino filtriramo in liofiliziramo. Dobimo amorfno natrijevo sol losartana v količini 3,10 g.3.10 g of the crystalline losartan sodium salt are dissolved in 31 ml of water. The clear solution was filtered and lyophilized. The amorphous sodium salt of losartan is obtained in an amount of 3.10 g.
Tališče: 171-177 °CMelting point: 171-177 ° C
Poskus 21Experiment 21
Trden farmacevtski pripravek, ki vsebuje kalijevo sol losartanaA solid pharmaceutical preparation containing the losartan potassium salt
Pripravili smo filmsko obložene tablete, ki v jedru vsebujejo:We have prepared film-coated tablets containing:
-3030 titanov dioksid smukec-3030 titanium dioxide talc
0,920 mg 0,200 mg0,920 mg 0,200 mg
Tablete smo pripravili po postopku direktne suhe zmesi. Učinkovino smo zmešali z laktozo, mikrokristalno celulozo, škrobom in aerosilom in zmes presejali. Dodali magnezijev stearat in vse skupaj ponovno zmešali. Tabletirali smo jedra z maso 160 mg. Na jedra smo nanesli filmsko oblogo pripravljeno iz naštetih sestavin kot suspenzijo v demineralizirani vodi. Obložene tablete smo polirali s smukcem.The tablets were prepared by the direct dry mixture process. The active substance was mixed with lactose, microcrystalline cellulose, starch and aerosil and the mixture was screened. Magnesium stearate added and mixed again. 160 mg tablets were tableted. A film coating prepared from the above ingredients was applied to the cores as a suspension in demineralized water. The coated tablets were polished with talc.
Poskus 22Experiment 22
Trden farmacevtski pripravek, ki vsebuje kalijevo sol losartana in hidroklorotiazidA solid pharmaceutical preparation containing the losartan potassium salt and hydrochlorothiazide
Tablete vsebujoče v jedru naslednje sestavine:Tablets containing the following ingredients at the core:
granulat homogenizirali. Tabletirali smo jedra z maso 175 mg. Na jedra smo nanesli filmsko oblogo pripravljeno iz naštetih sestavin kot suspenzijo v demineralizirani vodi. Filmsko obložene tablete smo polirali s smukcem.granulate homogenized. 175 mg tablets were tableted. A film coating prepared from the above ingredients was applied to the cores as a suspension in demineralized water. The film-coated tablets were polished with talc.
Claims (26)
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI200300025A SI21423A (en) | 2003-01-30 | 2003-01-30 | Preparation of new pharmaceutically applicable forms of losartan by new methods of purification and isolation |
AT04706411T ATE487478T1 (en) | 2003-01-30 | 2004-01-29 | PRODUCTION OF A NEW PHARMACEUTICALLY APPLICABLE LOSARTAN SALT AND ITS FORMS USING NEW PURIFICATION AND ISOLATION METHODS |
DE602004029982T DE602004029982D1 (en) | 2003-01-30 | 2004-01-29 | PREPARATION OF A NEW PHARMACEUTOLIZED LOSARTANE SALT AND ITS FORMS THROUGH NEW CLEANING AND INSULATION METHODS |
PCT/SI2004/000001 WO2004066997A2 (en) | 2003-01-30 | 2004-01-29 | Preparation of new pharmaceutically suitable salt of losartan and forms thereof with new purification and isolation methods |
SI200431599T SI1589966T1 (en) | 2003-01-30 | 2004-01-29 | Preparation of new pharmaceutically suitable salt of losartan and forms thereof with new purification and isolation methods |
EP04706411A EP1589966B1 (en) | 2003-01-30 | 2004-01-29 | Preparation of new pharmaceutically suitable salt of losartan and forms thereof with new purification and isolation methods |
US10/524,993 US7271269B2 (en) | 2003-01-30 | 2004-01-29 | Preparation of new pharmaceutically suitable salt of losartan and forms thereof with new purification and isolation methods |
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SI200300025A SI21423A (en) | 2003-01-30 | 2003-01-30 | Preparation of new pharmaceutically applicable forms of losartan by new methods of purification and isolation |
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