SI21121A

SI21121A - Amlodipine free base

Info

Publication number: SI21121A
Application number: SI200200028A
Authority: SI
Inventors: Theodorus Hendricus Antonius Peters; Franciscus Bernardus Gemma Benneker; Jacobus Maria Lemmens; Rolf Keltjens
Original assignee: Synthon Licensing, Ltd.
Priority date: 2002-02-05
Filing date: 2002-02-05
Publication date: 2003-08-31

Abstract

Amlodipine free base can be formulated into a convenient oral dosage form, especially a tablet, without excessive stickiness or tablet punch residue. The amlodipine free base can be crystalline Form I or a novel Form II. Methods of making and using the amlodipine free base are set forth

Description

1. Področje izuma1. FIELD OF THE INVENTION

Predloženi izum se nanaša na prosto bazo amlodipina, na sestavke, ki vsebujejo prosto bazo amlodipina, in na uporabo proste baze amlodipina v terapiji.The present invention relates to a free base of amlodipine, to compositions containing a free base of amlodipine, and to the use of a free base of amlodipine in therapy.

2. Opis sorodnega stanja tehnike2. Description of the prior art

EP 089 167 in ustrezen US 4,572,909 opisujeta razred substituiranih dihidropiridinskih derivatov kot uporabnih blokatorjev kalcijevih kanalov. Ta dva patenta identificirata, da je ena izmed najbolj prednostnih spojin 2-[(2aminoetoksi)metil]-4-(2-klorofenil)-3-etoksikarbonil-5-metoksikarbonil-6-metil-l,4dihidropiridin. Ta spojina, ki je sedaj običajno znana kot amlodipin, ima naslednjo formulo:EP 089 167 and corresponding US 4,572,909 describe a class of substituted dihydropyridine derivatives as useful calcium channel blockers. These two patents identify that one of the most preferred compounds is 2 - [(2aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, now commonly known as amlodipine, has the following formula:

Medtem ko je splošno opisan amlodipin kot prosta baza in kot farmacevtsko sprejemljiva kislinska adicijska sol, se vsi primeri amlodipina nanašajo na amlodipin maleat; npr. primeri 9, 11, 12 in 22 EP 089 167. Maleatna sol je identificirana kot najbolj prednostna kislinska adicijska sol. Presenetljivo ni okarakterizirana prosta baza amlodipina. Izgleda, da primeri opisujejo tvorbo proste baze, toda le kot raztopino/suspenzijo (primer 11) ali kot ostanek, ki ostane po uparitvi topila (primera 12 in 22). Opisana je le maleatna sol amlodipina, ki se obori iz raztopine (primera 12 in 22).While amlodipine is generally described as a free base and as a pharmaceutically acceptable acid addition salt, all examples of amlodipine refer to amlodipine maleate; e.g. Examples 9, 11, 12 and 22 EP 089 167. The maleate salt is identified as the most preferred acid addition salt. Surprisingly, amlodipine free base is not characterized. The examples appear to describe the formation of a free base, but only as a solution / suspension (Example 11) or as a residue that remains after solvent evaporation (Examples 12 and 22). Only the maleate salt of amlodipine precipitated from the solution is described (Examples 12 and 22).

Naknadno sta bila izdana EP 244 944 in ustrezen US 4,879,303, ki sta usmerjena k bezilatni (ali benzensulfonatni) soli amlodipina. Opisano je, da benzilatna sol zagotovi določene prednosti v primerjavi z znanimi solmi, ki vključujejo amlodipin maleat. Različne amlodipinske soli so primerjali na vodotopnost, stabilnost, ne-higroskopnost in sposobnost procesiranja za tvorbo tablet. Prosta baza amlodipina je bila vključena v testiranje sposobnosti procesiranja, ki je vključevalo merjenje količine amlodipina, ki ostane na tabletnem izsekovalniku po izdelavi tablet. Poročano je, da tablete proste baze amlodipina puščajo na izsekovalniku v povprečju 2,02 gg amlodipina/cm² na tableto. Za tablete amlodipin bezilata je poročano, da pustijo v povprečju 1,17 gg amlodipina/cm² na tableto. Torej je sestavek proste baze imel pomanjkljivost prekomerne lepljivosti na izsekovalnik tablet in ni bil primeren v izdelovanju trdnih dozirnih oblik za peroralno dajanje. Amlodipinska bezilatna sol je opisana v primerih 1 in 5, kjer naj bi bila izdelana iz suspenzijske proste baze amlodipina, čeprav ni opisan postopek, kako je bila prosta baza pripravljena.EP 244 944 and the corresponding US Patent 4,879,303 were subsequently issued targeting the besylate (or benzenesulfonate) salt of amlodipine. The benzylate salt has been described to provide certain advantages over the known salts, which include amlodipine maleate. Different amlodipine salts were compared for water solubility, stability, non-hygroscopicity, and processing capability for tablet formation. The free base of amlodipine was included in the processing capability testing, which included measuring the amount of amlodipine left on the tablet punch after making the tablets. Amlodipine free base tablets have been reported to leak on the puncture machine an average of 2.02 gg amlodipine / cm ² per tablet. Amlodipine besylate tablets have been reported to leave an average of 1.17 gg amlodipine / cm ² per tablet. Therefore, the free base composition had the disadvantage of over-sticking to the tablet punch and was not suitable for making solid dosage forms for oral administration. The amlodipine besylate salt is described in Examples 1 and 5, where it is said to be made from the suspension free base of amlodipine, although the procedure for how the free base was prepared is not described.

D.M. McDaid in P.B. Deasy v Int. H. of Pharmaceutics 133, 71-83 (1996) predlagata uporabo proste baze amlodipina v transdermalnem farmacevtiku kot je obliž. V gornjem članku je bila prosta baza amlodipina pripravljena v trdnem stanju, njena struktura je bila potrjena z NMR in okarakterizirana s tališčem 144 °C in topnostjo v vodi 77,4 mg/1. Trdna amlodipinska baza je bila pripravljena z nevtralizacijo raztopine amlodipin bezilata z natrijevim hidroksidom. V prvem postopku je bil bezilat raztopljen v metanolu pri 20 °C, dodan je bil vodni natrijev hidroksid in baza je bila ekstrahirana iz zmesi z dietiletrom, ki je bil nato uparjen. Omeniti je potrebno, da ta postopek, kot je opisan, ni ponovljiv, saj se dietileter meša z reakcijsko zmesjo. V drugem postopku je bila vodna raztopina bezilata obdelana pri 50 °C z raztopino natrijevega hidroksida in baza je izkristalizirala po ohladitvi na 4 °C.D.M. McDaid and P.B. Deasy v Int. H. of Pharmaceutics 133, 71-83 (1996) propose the use of a free base of amlodipine in a transdermal pharmaceutical such as a patch. In the above article, the free base of amlodipine was prepared in the solid state, its structure was confirmed by NMR and characterized by a melting point of 144 ° C and a water solubility of 77.4 mg / l. A solid amlodipine base was prepared by neutralizing a solution of amlodipine besylate with sodium hydroxide. In the first process, the besylate was dissolved in methanol at 20 ° C, aqueous sodium hydroxide was added, and the base was extracted from the mixture with diethyl ether, which was then evaporated. It should be noted that this process, as described, is not reproducible since diethyl ether is miscible with the reaction mixture. In the second process, the aqueous besylate solution was treated at 50 ° C with sodium hydroxide solution and the base crystallized after cooling to 4 ° C.

Želeno bi bilo imeti amlodipinsko oralno dozirno obliko, ki bi temeljila na prosti bazi amlodipina. Takšna dozirna oblika bi bila prednostno ekvivalent oblikam amlodipinske kislinske adicijske soli, še zlasti tržni amlodipin bezilatni soh in ne bi smela imeti znatnih pomankljivosti pri izdelavi ali problemov s stabilnostjo. Nadalje bi bilo zaželeno zagotoviti neposredno metodo za tvorbo proste baze amlodipina, ki bi omogočila izolacijo z, med drugim, filtracijo.It would be desirable to have an amlodipine oral dosage form based on the free base of amlodipine. Such a dosage form would preferably be equivalent to the forms of the amlodipine acid addition salt, in particular the marketed amlodipine besylate soh, and should not have significant manufacturing defects or stability problems. Furthermore, it would be desirable to provide a direct method for the formation of a free base of amlodipine that would allow isolation by, inter alia, filtration.

POVZETEK IZUMASUMMARY OF THE INVENTION

Predloženi izum temelji na študiji proste baze amlodipina in odkritju njenih različnih fizikalnih lastnosti. Iz realizacije teh lastnosti predloženi izum zagotavlja uporabno farmacevtsko dozirno obliko proste baze amlodipina, še zlasti tableto, novo kristalno obliko proste baze amlodipina, populacijo delcev proste baze amlodipina, ki so uporabni pri izdelovanju tablete in na postopek za bolj ekonomično tvorbo proste baze amlodipina. Torej se prvi vidik predloženega izuma nanaša na farmacevtski tabletni sestavek, ki obsega učinkovito količino proste baze amlodipina in vsaj en farmacevtsko sprejemljiv ekscipient; pri čemer tableta izraža nizek izsekovalni ostanek, kot je definiran tu v nadaljevanju. Prednostno tableta pusti povprečni ostanek na tabletnem izsekovalniku 0,7 pg.cm' na tableto ali manj.The present invention is based on the study of the free base of amlodipine and the discovery of its various physical properties. In order to realize these properties, the present invention provides a useful amlodipine free base pharmaceutical dosage form, in particular a tablet, a new crystalline amlodipine free base, a population of amlodipine free base particles useful in the manufacture of a tablet and a process for the more economical formation of an amlodipine free base. Thus, the first aspect of the present invention relates to a pharmaceutical tablet composition comprising an effective amount of the free base of amlodipine and at least one pharmaceutically acceptable excipient; wherein the tablet expresses a low puncture residue as defined hereinbelow. Preferably, the tablet leaves an average residue on the tablet puncher of 0.7 pg.cm 'per tablet or less.

Drug vidik predloženega izuma se nanaša na kristalno prosto bazo amlodipina oblikeAnother aspect of the present invention relates to the crystalline free base of amlodipine form

II. Ta nova kristalna oblika amlodipina je primerna tudi za uporabo kot farmacevtsko aktivno sredstvo.II. This novel crystalline form of amlodipine is also suitable for use as a pharmaceutically active agent.

Se en vidik predloženega izuma se nanaša na populacijo delcev proste baze amlodipina, ki imajo povprečno velikost delcev vsaj 100 mikrometrov. Prednostno so delci kristali in povprečna velikost delcev je 150 do 350 mikrometrov. Takšna populacija delcev je uporabna v tvorbi tabletnega sestavka.Another aspect of the present invention relates to a population of amlodipine free base particles having an average particle size of at least 100 micrometers. Preferably, the particles are crystals and the average particle size is 150 to 350 micrometers. Such a population of particles is useful in the formation of a tablet composition.

Nadaljnji vidik izuma se nanaša na postopek zdravljenja ali preprečevanja hipertenzije, angine ali kongestivne odpovedi srca, ki obsega dajanje učinkovite količine proste baze amlodipina pacientu, ki jo potrebuje. Prednostno dajemo prosto bazo amlodipina v zgoraj omenjeni tabletni obliki.A further aspect of the invention relates to a method of treating or preventing hypertension, angina or congestive heart failure, comprising administering to the patient in need thereof an effective amount of the free base of amlodipine. Preferably, the free base of amlodipine is administered in the tablet form mentioned above.

Še nadaljnji vidik predloženega izuma se nanaša na postopek, ki obsega odstranitev zaščite N-zaščitenemu amlodipinu s sredstvom za odstranitev zaščite, da se tvori prosta baza amlodipina; obarjanje navedene proste baze amlodipina iz raztopine; in izoliranje navedene oborjene proste baze amlodipina v trdni obliki. Raztopina, iz katere se obori prosta baza amlodipina, je lahko raztopina, ki je rezultat stopnje odstranitve zaščite, ali drugačna raztopina; t.j. v ekstrakcij skem topilu.A further aspect of the present invention relates to a process comprising removing the protection of N-protected amlodipine with a deprotecting agent to form the free base of amlodipine; precipitation of said free base of amlodipine from solution; and isolating said precipitated free base of amlodipine in solid form. The solution from which the free base of amlodipine precipitates may be a solution resulting from the degree of deprotection or a different solution; i.e. in the extraction solvent.

Še en vidik predloženega izuma se nanaša na postopek za čiščenje proste baze amlodipina, ki obsega: kristaliziranje proste baze amlodipina iz nevodnega topila. Prednostno kristalizacija proizvede kristale proste baze amlodipina, ki imajo povprečno velikost delcev 150 do 350 mikrometrov.Another aspect of the present invention relates to a process for the purification of a free base of amlodipine comprising: crystallizing the free base of amlodipine from a non-aqueous solvent. Preferably, crystallization produces free base crystals of amlodipine having an average particle size of 150 to 350 micrometers.

KRATEK OPIS RISBBRIEF DESCRIPTION OF THE DRAWINGS

Sl. 1 prikazuje rentgenski praškovni difraktogram za prosto bazo amlodipina (oblika I) referenčnega primera 3.FIG. 1 shows an X-ray powder diffractogram for the free base of amlodipine (Form I) of Reference Example 3.

Sl. 2 prikazuje IR spekter kristalne proste baze amlodipina (oblika I) primera 1.FIG. 2 shows the IR spectrum of the crystalline free base of amlodipine (Form I) of Example 1.

Sl. 3 prikazuje DSC krivuljo kristalne proste baze amlodipina (oblika I) primera 1.FIG. 3 shows the DSC curve of the crystalline free base of amlodipine (Form I) of Example 1.

Sl. 4 prikazuje IR spekter kristalne proste baze amlodipina (oblika I) primera 4a.FIG. 4 shows the IR spectrum of the crystalline free base of amlodipine (Form I) of Example 4a.

Sl. 5 prikazuje DSC krivuljo kristalne proste baze amlodipina (oblika I) primera 4a.FIG. 5 shows the DSC curve of the crystalline free base of amlodipine (Form I) of Example 4a.

Sl. 6 prikazuje IR spekter kristalne proste baze amlodipina (oblika II) primera 5a.FIG. 6 shows the IR spectrum of the crystalline free base of amlodipine (Form II) of Example 5a.

Sl. 7 prikazuje DSC krivuljo kristalne proste baze amlodipina (oblika II) primera 5a.FIG. 7 shows the DSC curve of the crystalline free base of amlodipine (Form II) of Example 5a.

Sl. 8 prikazuje rentgenski praškovni difraktogram kristalne proste baze amlodipina (oblika II) primera 5b.FIG. 8 shows an X-ray powder diffractogram of the crystalline free base of amlodipine (Form II) of Example 5b.

PODROBEN OPIS IZUMADETAILED DESCRIPTION OF THE INVENTION

Tableta proste baze amlodipina v smislu predloženega izuma je prednostno tableta z nizkim izsekovalnim ostankom. Nizek izsekovalni ostanek, kot ga uporabljamo tukaj, pomeni, da povprečna količina amlodipina, ki ostane na tabletnem izsekovalniku, ni večja od 1 pg/cm² na tableto, temelječ na 20 mm okroglem ploščatem izsekovalniku s silo stiskanja 15 kilonewtonov. Prednostno ima tableta povprečen izsekovalni ostanek 0,7 pg/cm² na tableto, bolj prednostno 0,6 pg/cm² na tableto. Količino amlodipinskega ostanka lahko merimo s postopkom, opisanim v EP 244 944. V splošnem postopek vključuje spiranje izsekovalnika po seriji 50, 100, 150, 200, 250 in 300 tablet z uporabo metanola in ultrazvočne kopeli. Količino amlodipina v vzorcih merimo z UV in celotno količino amlodipina, ekstrahirano iz obeh, gornjega in spodnjega izsekovalnika, izrišemo proti količini izdelanih tablet. Povprečno vrednost za amlodipinski ostanek (lepljivost) preračunamo iz naklona regresij ske premice s premikom y-odseka skozi nič.The amlodipine free base tablet of the present invention is preferably a tablet with a low excisional residue. The low puncture used as used here means that the average amount of amlodipine left on the tablet puncher is not more than 1 pg / cm ² per tablet based on a 20 mm round flat puncher with a compression force of 15 kilonewtons. Preferably, the tablet has an average puncture of 0.7 pg / cm ² per tablet, more preferably 0.6 pg / cm ² per tablet. The amount of amlodipine residue can be measured by the method described in EP 244 944. In general, the process involves washing the puncher out of a series of 50, 100, 150, 200, 250 and 300 tablets using methanol and an ultrasonic bath. The amount of amlodipine in the samples is measured by UV and the total amount of amlodipine extracted from both the upper and lower punches is plotted against the amount of tablets produced. The mean value for the amlodipine residue (stickiness) is calculated from the slope of the regression line by moving the y-section through zero.

Tableta obsega učinkovito količino proste baze amlodipina in vsaj en farmacevtsko sprejemljiv ekscipient. Ekscipient, kot ga uporabljamo tukaj, pomeni kakršnokoli farmacevtsko sprejemljivo neaktivno komponento sestavka. Kot je dobro znano v stroki, ekscipienti vključujejo razredčila, veziva, maziva, dezintegrante, barvila, antioksidante/konzervanse, sredstva za naravnavo pH itd. Ekscipienti so izbrani glede na želene fizikalne vidike končne oblike: npr. za pridobitev tablete z želeno trdoto in krhkostjo, da se hitro dispergira in se jo zlahka pogoltne itd. V izbiri ekscipientov igra vlogo tudi želena hitrost sproščanja aktivne snovi iz sestavka po njegovem zaužitju. Npr. pripravki so lahko, če je želeno, oblikovani tako, da dajo počasno sproščanje proste baze amlodipina.The tablet comprises an effective amount of amlodipine free base and at least one pharmaceutically acceptable excipient. Excipient as used herein means any pharmaceutically acceptable inactive component of the composition. As is well known in the art, excipients include diluents, binders, lubricants, disintegrants, colorants, antioxidants / preservatives, pH adjusters, etc. Excipients are selected according to the desired physical aspects of the final form: e.g. to obtain a tablet of the desired hardness and brittleness, to be quickly dispersed and easily swallowed, etc. The choice of excipients also plays a role in the desired rate of release of the active substance from the composition after ingestion. E.g. the preparations may, if desired, be formulated to give a slow release of the free base of amlodipine.

Ustrezni ekscipienti za uporabo v tem izumu vključujejo:Suitable excipients for use in the present invention include:

razredčilo, kot kalcijev hidrogen fosfat, laktozo, manitol itd.diluent such as calcium hydrogen phosphate, lactose, mannitol, etc.

vezivo, kot je mikrokristalna celuloza ali modificirana celuloza, povidon itd.a binder such as microcrystalline cellulose or modified cellulose, povidone, etc.

dezintegrant, kot je natrijev škrobni glikolat, krospovidon, mazivo, kot je magnezijev stearat, natrijev stearil fumarat, smukec, barvilo, sredstvo za maksiranje okusa itd.a disintegrant such as sodium starch glycolate, crospovidone, a lubricant such as magnesium stearate, sodium stearyl fumarate, talc, colorant, flavor enhancer, etc.

Tablete v smislu izuma prednostno ne zahtevajo kakršnegakoli sredstva proti lepljenju, kot je smukec. Sestava tablete prednostno obsega ekscipient kalcijev fosfat in/ali mikrokristalno celulozo in bolj prednostno tako kalcijev fosfat kot mikrokristalno celulozo. Primer ekscipienta kalcijevega fosfata je brezvodni kalcijev hidrogen fosfat. Poleg tega lahko tableta vsebuje druge konvencionalne ekscipiente, kot so veziva, maziva, dezintegranti, barvila, konzervansi itd.The tablets of the invention preferably do not require any adhesive such as talc. The composition of the tablet preferably comprises calcium phosphate excipient and / or microcrystalline cellulose and more preferably both calcium phosphate and microcrystalline cellulose. An example of a calcium phosphate excipient is anhydrous calcium hydrogen phosphate. In addition, the tablet may contain other conventional excipients such as binders, lubricants, disintegrants, colorants, preservatives, etc.

Prosta baza amlodipina je lahko kakršnekoli oblike, ki lahko vključuje kristalno obliko I, kristalno obliko II ali amorfno obliko. Oblika I je okarakterizirana s praškovnim rentgenskim difrakcijskim vzorcem kot je prikazan na sl. 1, IR spektrom, kot je prikazan na sl. 2 in 4, in z enim talilnim endotermom na DSC krivulji s pričetkom pri okoli 140 °C, kot je prikazano na sl. 3 in 5. Ta oblika ustreza materialu, ki sta ga opisala McDaid in Deasy. Oblika II je nova oblika in je okarakterizirana z distinktivnim praškovnim rentgenskim difrakcijskim vzorcem, kot je prikazan na sl. 8, IR spektrom, kot je prikazan na sl. 6, in z DSC krivuljo, za katero je značilen tranzicijski endoterm ali endo/eksoterm pri temperaturi okoli 100 °C, in talilni endoterm pri okoli 140 °C, kot je prikazano na sl. 7. Čeprav je možno, da se oblika II pretvori v obliko I z uporabo dovolj visokih temperatur, splošno nad 100 °C, je oblika II splošno stabilna pri sobnih pogojih in celo pri zmerno povišanih temperaturah. Npr., oblika II je stabilna po enem mesecu mirovanja pri 60 °C. Torej je oblika II uporabna v izdelavi farmacevtskih končnih oblik. Prosta baza amlodipina v tableti v smislu predloženega izuma je lahko enojnega tipa ali pa je lahko zmes. Na primer zmes kristalnih oblik I in II.The free base of amlodipine may be of any form, which may include crystalline form I, crystalline form II, or amorphous form. Form I is characterized by a powder X-ray diffraction pattern as shown in FIG. 1, IR spectrum as shown in FIG. 2 and 4, and with one melting endotherm on the DSC curve starting at about 140 ° C, as shown in FIG. 3 and 5. This design corresponds to the material described by McDaid and Deasy. Form II is a new form and is characterized by a distinctive powder X-ray diffraction pattern as shown in FIG. 8, the IR spectrum as shown in FIG. 6, and with a DSC curve characterized by a transition endotherm or endo / exotherm at a temperature of about 100 ° C, and a melting endotherm at about 140 ° C, as shown in FIG. 7. Although it is possible for Form II to be converted to Form I using sufficiently high temperatures, generally above 100 ° C, Form II is generally stable under room conditions and even at moderately elevated temperatures. For example, Form II is stable after one month of rest at 60 ° C. Thus, Form II is useful in the manufacture of pharmaceutical finished forms. The free base of amlodipine in the tablet of the present invention may be of a single type or may be a mixture. For example, a mixture of crystalline forms I and II.

Za zmanjšanje lepljivosti tablet je splošno želeno, da kontroliramo velikost proste baze amlodipina in/ali uporabljenih ekscipientov. Specifično je prednostno, da je prosta baza amlodipina vključena v tabletni sestavek v obliki delcev, ki imajo povprečno velikost delcev vsaj 100 mikrometrov, prednostno 150 do 350 mikrometrov, bolj prednostno 200 do 300 mikrometrov. Delci so splošno kristali proste baze amlodipina, čeprav so vključene tudi nekristalne oblike. Vlaga v tableti je prednostno omejena, da se zmanjša lepljivost. Prednostna ekscipienta sta kalcijev fosfat in mikrokristalna celuloza, kot je opisano zgoraj.In order to reduce the stickiness of the tablets, it is generally desirable to control the size of the free base of amlodipine and / or excipients used. It is specifically preferred that the free base of amlodipine is included in a tablet composition in the form of particles having an average particle size of at least 100 micrometers, preferably 150 to 350 micrometers, more preferably 200 to 300 micrometers. The particles are generally crystals of the free base of amlodipine, although non-crystalline forms are also included. Moisture in the tablet is preferably limited to reduce stickiness. Preferred excipients are calcium phosphate and microcrystalline cellulose as described above.

Količina proste baze amlodipina ni posebej omejena in vključuje kakršnokoli količino, ki zagotovi farmacevtski učinek. Še zlasti lahko prosto bazo amlodipina uporabimo za zdravljenje ali preprečevanje hipertenzije, kongestivne odpovedi srca ali angine z dajanjem učinkovite količine pacientu, ki jo potrebuje. Specifična oblika angine ni posebej omejena in specifično vključuje kronično stabilno angino pectoris in vazospastično angino (Prinzmetalovo angino). Pacienti, ki jih nameravamo zdraviti, vključujejo ljudi in živali, še zlasti ljudi in živali sesalce. Splošno je količina proste baze amlodipina v enotski dozi od 1 do 100 mg, bolj tipično od 1 do 25 mg in prednostno okoli 1, 1,25, 2,5, 5 ali 10 mg. Izraženo relativno je količina proste baze amlodipina v sestavku lahko prednostno med 2 in 10 %.The amount of free base of amlodipine is not particularly limited and includes any amount that provides a pharmaceutical effect. In particular, the free base of amlodipine may be used to treat or prevent hypertension, congestive heart failure or angina by administering an effective amount to a patient in need. The specific form of angina is not particularly limited and specifically includes chronic stable angina pectoris and vasospastic angina (Prinzmetal angina). The patients we intend to treat include humans and animals, especially humans and animals, mammals. In general, the amount of free base of amlodipine in a unit dose is from 1 to 100 mg, more typically from 1 to 25 mg, and preferably about 1, 1.25, 2.5, 5 or 10 mg. Expressed relatively, the amount of free base of amlodipine in the composition may preferably be between 2 and 10%.

Prosta baza amlodipina, uporabljena v tableti v smislu predloženega izuma, je lahko izdelana s kakršnimikoli ustreznimi sredstvi. Prednostno prosto bazo tvorimo in izoliramo s postopkom, ki obsega odstranitev zaščite N-zaščitenemu amlodipinu s sredstvom za odstranitev zaščite, da tvorimo prosto bazo amlodipina; obarjanje navedene proste baze amlodipina iz raztopine; in izolacijo navedene oborjene proste baze amlodipina v obliki trdnega stanja. N-zaščiten amlodipin je amlodipinska spojina, kjer je končna amino skupina zaščitena kot je prikazano v formuli (2):The free base of amlodipine used in the tablet of the present invention may be manufactured by any suitable means. Preferably the free base is formed and isolated by a method comprising removing the protection of N-protected amlodipine with a deprotecting agent to form the free base of amlodipine; precipitation of said free base of amlodipine from solution; and isolating said precipitated free base amlodipine in solid form. N-protected amlodipine is an amlodipine compound where the amino terminal group is protected as shown in formula (2):

kjer N-prot pomeni amino skupino, zaščiteno z odcepljivo zaščitno skupino, kot je benzilna skupina ali tritilna skupina, ali maskirano s skupino, ki se jo da pretvoriti v amino skupino, kot je ftalimido skupina ali azido skupina. V prednostni izvedbi je zaščiten amlodipin ftalimido-zaščitena amlodipinska spojina s formulo (2a):wherein the N-prot represents an amino group protected by a cleavable protecting group such as a benzyl group or a trityl group, or masked by a group which can be converted to an amino group such as a phthalimido group or an azido group. In a preferred embodiment, the protected amlodipine phthalimido-protected amlodipine compound of formula (2a) is:

h₃c-ch ₃ cc

Ό ο,Ό ο,

.o-ch₂-ch₃° (2a)..o-ch ₂ -ch ₃ ° (2a).

Ta zaščiten amlodipin je pogosto tu v nadaljevanju naveden kot ftalodipin.This protected amlodipine is often referred to hereinafter as phthalodipine.

V smislu izuma je lahko prosta baza amlodipina pripravljena v trdnem stanju z ustrezno obdelavo reakcijske zmesi, ki jo dobimo po zadnjem sinteznem koraku, ki vodi do amlodipina; namreč koraku, ki obsega odstranitev zaščite amlodipinskemu prekurzorju z gornjo formulo (2). Ustrezna sredstva za odstranitev zaščite so dobro znana v stroki in njihova izbira je odvisna od zaščitne skupine, ki jo uporabimo. Prosto bazo amlodipina dobimo ne da bi bilo potrebno tvoriti, in še zlasti izolirati, amlodipinsko sol. Za postopek je značilno, da se ne za odstranitev zaščite, kot tudi ne za namene izdelave, ne uporabi kislinsko sredstvo ali medij; t.j. prosta baza amlodipina, ki se tvori z odstranitvijo zaščite, je prosta baza, ki se obori brez vmesne stopnje tvorbe amlodipinske soli.According to the invention, the free base of amlodipine can be prepared in the solid state by suitable treatment of the reaction mixture obtained after the last synthesis step leading to amlodipine; namely, a step comprising removing the protection of the amlodipine precursor of the above formula (2). Suitable deprotecting agents are well known in the art and their choice depends on the protecting group used. The free base of amlodipine is obtained without the need to form, and in particular isolate, the amlodipine salt. The process is characterized by the fact that no acidic agent or medium is used to remove the protection as well as for the purpose of manufacture; i.e. the free base of amlodipine formed by deprotection is a free base that precipitates without an intermediate stage of amlodipine salt formation.

Postopek v smislu predloženega izuma zahteva obarjanje proste baze amlodipina iz raztopine. Obarjanje je dobro znan fenomen, pri katerem se trdna faza loči od raztopine. Prednost obarjanja je, da lahko trdno fazo, ki vsebuje želen produkt, ločimo od tekoče faze, ki vsebuje topilo in topne so-produkte, t.j. stranske produkte ali nečistote.The process of the present invention requires the precipitation of the free base of amlodipine from solution. Precipitation is a well-known phenomenon in which the solid phase is separated from the solution. The advantage of precipitation is that the solid phase containing the desired product can be separated from the liquid phase containing the solvent and soluble co-products, i.e. by-products or impurities.

Obarjanje je tako tudi orodje, da se znebimo vsaj nekaterih nečistot iz produkta. To ni možno, če dobimo trden produkt iz raztopine z enostavnim uparevanjem topila. Tako za namene predloženega izuma obarjanje ne vključuje odparevanje vsega topila v raztopini, da ostane ostanek. Obarjanje je prednostno kristalizacija, čeprav nanjo ni omejeno. Obarjanje, ki vključuje zmanjšanje temperature raztopine, splošno vodi do kristalizacije, medtem ko obarjanje, ki vključuje spremembo v pH, lahko vodi do bolj klasičnega obarjanja trdne snovi, bodisi v kristalni ali nekristalni obliki. Raztopino lahko tvorimo neposredno s korakom odstranitve zaščite, ali pa je lahko drugačna raztopina, takšna, kot je tista, ki se tvori z ekstrakcijskim postopkom. Raztopina je lahko vodna, nevodna ali je zmes topil. Splošno vodno topilo vodi do tvorbe delcev majhne velikosti. Korak čiščenja, ki je opisan tu dalje, lahko uporabimo, če je želeno, za pridobitev delcev proste baze amlodipina z večjo velikostjo.The precipitate is also a tool to get rid of at least some of the impurities from the product. This is not possible if a solid product is obtained from the solution by simply evaporating the solvent. Thus, for the purposes of the present invention, precipitation does not involve evaporation of all the solvent in solution to remain a residue. Precipitating is preferably crystallization, although not limited to it. Precipitation, which involves a decrease in the temperature of the solution, generally leads to crystallization, whereas precipitation, involving a change in pH, can lead to more classical precipitation of the solid, whether in crystalline or non-crystalline form. The solution may be formed directly by the removal step of the protection, or it may be a different solution such as that formed by the extraction process. The solution may be aqueous, non-aqueous or a mixture of solvents. A general aqueous solvent leads to the formation of small particles. The purification step described hereinafter can be used, if desired, to obtain larger-sized amlodipine free base particles.

Izolacijo oborjene trdne oblike proste baze amlodipina lahko izvedemo s kakršnokoli ustrezno ali znano tehniko za ločevanje trdne faze od tekoče faze, t.j. topila ali raztopine. Prednostno izolacijski korak uporablja filtracijo.The isolation of the precipitated solid form of the free base of amlodipine can be carried out by any suitable or known technique for separating the solid phase from the liquid phase, i.e. solvents or solutions. Preferably, the isolation step uses filtration.

Izum bomo opisali glede na njegovo prednostno izvedbo, v kateri se ftalodipin s formulo (2a) uporabi kot N-zaščitena amlodipinska spojina. Po EP 89167 se ftalodipinu odstrani zaščita bodisi z etanolnim metilaminom, etanolnim hidrazinhidratom ali z KOH v zmesi voda/tetrahidrofuran. Te tehnike so primerne za postopek v smislu našega izuma, vendar pa so dokaj neekonomične. V bolj ugodnem načinu izvedemo odstranitev zaščite z obdelavo ftalodipina z vodno raztopino metilamina. Prednost vodne raztopine metilamina je, da se prosta baza amlodipina enostavno loči od reakcijske zmesi in dajo lahko enostavno izoliramo v trdnem stanju s filtracijo. So-produkt reakcije odstranitve zaščite (N-metilftalamid) ostane v vodni raztopini.The invention will be described according to a preferred embodiment in which the phthalodipine of formula (2a) is used as the N-protected amlodipine compound. According to EP 89167, phthalodipine is deprotected with either ethanol methylamine, ethanol hydrazine hydrate or KOH in a water / tetrahydrofuran mixture. These techniques are suitable for the process of the present invention, but are quite uneconomical. In a more advantageous manner, removal of the protection is performed by treating the phthalodipine with an aqueous methylamine solution. The advantage of an aqueous methylamine solution is that the free base of amlodipine is easily separated from the reaction mixture and can be easily isolated in the solid state by filtration. The co-product of the deprotection reaction (N-methylphthalamide) remains in aqueous solution.

Reakcijo z vodnim metilaminom lahko izvedemo pri temperaturi od sobne do okoli 60°C, prednostno pri 3O-5O°C. Seveda lahko reakcijo nadzorujemo s katerokoli ustrezno analizno tehniko, ki omogoča ločevanje izhodnega materiala in produkta npr. HPLC. Produkt lahko ločimo s filtracijo pri 5-25 °C, prednostno pri sobni temperaturi.The reaction with aqueous methylamine can be carried out at room temperature to about 60 ° C, preferably at 3O-5O ° C. Of course, the reaction can be controlled by any suitable analytical technique that allows the separation of starting material and product, e.g. HPLC. The product can be separated by filtration at 5-25 ° C, preferably at room temperature.

V alternativnem načinu lahko reakcijsko zmes, ki obsega prosto bazo amlodipina, izdelamo z ekstakcijo amlodipina iz alkalne vodne raztopine z organskim topilom, ki se ne meša z vodo, npr. toluenom. Temperatura ekstrakcije je v bistvu sobna. Koncentracija ekstrakcijske raztopine omogoči obarjanje surove proste bazeIn an alternative mode, a reaction mixture comprising the free base of amlodipine can be prepared by extracting amlodipine from an alkaline aqueous solution with a water-immiscible organic solvent, e.g. toluene. The extraction temperature is essentially room temperature. The concentration of the extraction solution allows the crude free base to precipitate

-1010 amlodipina v trdnem stanju. Da olajšamo obarjanje proste baze amlodipina v trdnem stanju, lahko k ekstakcijski raztopini, še zlasti koncentrirani raztopini, dodamo kontratopilo (npr. heksan),-1010 solid-state amlodipine. To facilitate precipitation of the free base of amlodipine in the solid state, a counter-solvent (eg hexane) may be added to the extraction solution, especially the concentrated solution,

Surovo trdno prosto bazo amlodipina lahko nadalje očistimo z različimi tehnikami. Navesti je potrebno, da pomen surov trden amlodipin ni omejen le na trdno amlodipinsko bazo, pripravljeno po gornjem postopku našega izuma, ampak vključuje kakršnokoli trdno amlodipinsko bazo, ki jo je potrebno nadalje očistiti. Čiščenje je tukaj uporabljeno v širokem smislu, da vključuje izboljšanje velikosti kristalov, t.j. odstranjevanje majhnih kristalov v korist večjih kristalov, kot tudi zmanjšanje nivoja kontaminantov v prosti bazi amlodipina. Obarjanje iz vodnih raztopin še zlasti splošno proizvede prosto bazo amlodipina kot fine delce. Čiščenje s korakom čiščenja kristalizacijo lahko uporabimo za pridobitev kristalov proste baze amlodipina, ki imajo večjo, bolj želeno velikost delcev.The crude solid free base of amlodipine can be further purified by various techniques. It should be noted that the meaning of crude solid amlodipine is not limited to the solid amlodipine base prepared according to the process of the present invention, but includes any solid amlodipine base that needs to be further purified. Purification is used herein broadly to include enhancement of the size of crystals, i.e. the removal of small crystals in favor of larger crystals, as well as the reduction of contaminants in the free base of amlodipine. Precipitation from aqueous solutions, in particular, generally produces the free base of amlodipine as fine particles. Purification by purification step crystallization can be used to obtain free base crystals of amlodipine having a larger, more desirable particle size.

V prvi čistilni metodi prosto bazo amlodipina kristaliziramo iz raztopine, ki temelji na ustreznem nevodnem topilu, včasih tu dalje navedenem kot čistilno topilo. Prednostno izvedemo raztapljanje amlodipina v topilu pod povišano temperaturo, ki lahko obsega celo temperaturo vrelišča čistilnega topila. Če je želeno, lahko dobljeno raztopino še pred kristalizacijo nadalje očistimo s konvencionalnimi adsorpcijskimi tehnikami, npr. z obdelavo z aktivnim ogljem ali silikagelom. Kristalizacijo iz raztopine lahko izvedemo po različnih poteh:In the first purification method, the free base of amlodipine is crystallized from a solution based on a suitable non-aqueous solvent, sometimes referred to here as a purification solvent. Preferably, the dissolution of amlodipine in the solvent is carried out under an elevated temperature, which may comprise the entire boiling point of the cleaning solvent. If desired, the resulting solution can be further purified by conventional adsorption techniques prior to crystallization, e.g. by treatment with activated carbon or silica gel. Crystallization from the solution can be carried out in different ways:

s spontanim ali vsiljenim ohlajanjem raztopine proste baze amlodipina z dodajanjem kontra-topila, ki se vsaj delno meša, k raztopini proste baze amlodipina (ob mešanju ali ob difuziji), po izbiri v kombinaciji s spontanim ali vsiljenim ohlajanjem z uparevanjem dela topila, po izbiri v kombinaciji z katerokoli od predhodnih tehnik.by spontaneously or forced cooling of the free base solution of amlodipine by adding at least partially miscible counter-solvent to the free base solution of amlodipine (by mixing or diffusion), optionally in combination with spontaneous or forced cooling by evaporation of a portion of the solvent, optionally in combination with any of the foregoing techniques.

Ustrezna topila obsegajo alifatske C1-C4 alkohole, kot je metanol ali etanol, klorirane C1-C4 ogljikovodike, kot je kloroform, alkilestre alifatskih kislin, kot je etilacetat, nitrile alifatskih kislin, kot je acetonitril, aromatske ogljikovodike, kot je toluen,Suitable solvents include aliphatic C1-C4 alcohols such as methanol or ethanol, chlorinated C1-C4 hydrocarbons such as chloroform, aliphatic acid alkyl esters such as ethyl acetate, aliphatic acid nitriles such as acetonitrile, aromatic hydrocarbons such as toluene,

-1111-1111

C1-C6 ketone, kot aceton in njihove zmesi. Ustrezna kontra-topila so lahko bodisi bolj polama kot topilo; primer je voda, ali pa manj polama kot topilo; primer je heksan ali heptan.C1-C6 ketones, such as acetone and mixtures thereof. Suitable counter-solvents can be either more polym than the solvent; an example is water, or less polam than a solvent; an example is hexane or heptane.

V še eni metodi čiščenja surovo bazo amlodipina raztopimo v ustreznem čistilnem topilu, ki se z vodo ne meša ali se z vodo slabo meša, npr. v toluenu, toluensko raztopino ekstrahiramo z vodno kislino, da zagotovimo vodno raztopino amlodipinske soli, ki jo nato nevtraliziramo z bazo, npr. alkalijsko ali aminom. Tvorjeno amlodipinsko bazo lahko oborimo iz vodne raztopine in jo lahko ločimo, ali pa jo ekstrahiramo nazaj v organsko topilo, ki se ne meša z vodo ali se z vodo slabo meša, katero nato ohladimo, koncentriramo ali zmešamo s kontra-topilom, pri čemer se očiščena prosta baza amlodipina obori iz raztopine. Narava kisline mora biti prednostno izbrana tako, da je tvorjena amlodipinska sol topna v vodi. Ustrezna kislina je klorovodikova kislina.In another purification method, the crude base of amlodipine is dissolved in a suitable water-immiscible or poorly miscible cleaning solvent, e.g. in toluene, the toluene solution is extracted with aqueous acid to provide an aqueous solution of the amlodipine salt, which is then neutralized with a base, e.g. alkali or amine. The formed amlodipine base can be precipitated from an aqueous solution and can be separated or extracted back into a water-immiscible or poorly miscible organic solvent which is then cooled, concentrated or mixed with a counter-solvent, whereby purified free base of amlodipine precipitates from solution. The nature of the acid should preferably be chosen such that the formed amlodipine salt is soluble in water. Suitable acid is hydrochloric acid.

Prosto bazo amlodipina v trdni obliki lahko pripravimo tudi z liofilizacijo njene raztopine, npr. raztopine v etanolu-vodi (2:1).The free base of amlodipine in solid form can also be prepared by lyophilization of its solution, e.g. solutions in ethanol-water (2: 1).

S katerokoli od gornjih proizvodnih ali čistilnih metod, razen kadar delamo pod pogoji, ki jih bomo obravnavali spodaj, dobimo prosto bazo amlodipina v kristalni obliki I.By any of the above manufacturing or purification methods, except when operated under the conditions discussed below, free crystalline Form I amlodipine is obtained.

Pod določenimi pogoji lahko novo polimorfno obliko proste baze amlodipina (obliko II) v trdnem stanju pripravimo iz raztopin proste baze amlodipina. Splošno pogoji zahtevajo, da se kristalizacija prične pri nizkih temperaturah in značilno ob hitrem ohlajanju, da se izognemo tvorbi jeder oblike I. Npr., oblika II se tvori, če raztopino proste baze amlodipina v nevodnem topilu, npr. v toluenu, obdelamo s kontra-topilom, npr. s heksanom, cikloheksanom ali heptanom, pri temperaturah pod 5°C. Raztopina proste baze amlodipina v nevodnem topilu vključuje surovo raztopino, npr. toluensko raztopino, dobljeno po gornjem koraku odstranitve zaščite. Dodajanje kontra-topila vključuje dodajanje kontra-topila v ohlajeno ali ohlajano raztopino proste baze amlodipina ali dodajanje raztopine proste baze amlodipina k ohlajenem kontra-topilu.Under certain conditions, a new polymorphic form of the free base of amlodipine (Form II) in the solid state can be prepared from solutions of the free base of amlodipine. General conditions require crystallisation to start at low temperatures and typically upon rapid cooling to avoid formation of Form I cores. For example, Form II is formed when a solution of the free base of amlodipine in a non-aqueous solvent, e.g. in toluene, treated with a counter-solvent, e.g. with hexane, cyclohexane or heptane, at temperatures below 5 ° C. The free base solution of amlodipine in a non-aqueous solvent includes a crude solution, e.g. toluene solution obtained after the above deprotection step. Adding a counter-solvent involves adding a counter-solvent to a cooled or chilled amlodipine free base solution or adding a free amlodipine base solution to a cooled counter-solvent.

-1212-1212

Splošno uporaba kontra-topila dopušča uporabo višje kristalizacij ske temperature v tvorbi oblike II.In general, the use of a counter-solvent permits the use of higher crystallization temperatures in Form II formation.

V alternativnem postopku lahko obliko II tvorimo z obarjanjem po vsiljenem ohlajanju raztopine proste baze amlodipina v ustreznem kristalizacij skem topilu, npr. etilacetatu, kjer se obarjanje začne pri temperaturi pod 5°C, bolj prednostno pod -5°C in bolj običajno pri -10°C ali pod vključno -20 °C in še nižje.In an alternative process, Form II can be formed by precipitation upon forced cooling of the amlodipine free base solution in a suitable crystallization solvent, e.g. ethyl acetate, where precipitation begins at a temperature below 5 ° C, more preferably below -5 ° C, and more commonly at -10 ° C or below and -20 ° C, and even lower.

Omeniti je potrebno, da lahko prosto bazo amlodipina, še zlasti kristalno prosto bazo amlodipina oblike II in očiščeno prosto bazo amlodipina opisano zgoraj, uporabimo tudi kot intermediat v proizvodnji amlodipinskih kislinskih adicijskih soli. V ugodnem načinu amlodipinsko bazo, očiščeno z metodami tega izuma, reagiramo s farmacevtsko sprejemljivo kislino, da se tvori amlodipinska sol, ki izraža želeno stopnjo čistote, npr. farmacevtsko čistoto, ne da bi jo bilo potrebno nadalje čistiti.It should be noted that the free base of amlodipine, in particular the crystalline free base of amlodipine form II and the purified free base of amlodipine described above, can also be used as an intermediate in the production of amlodipine acid addition salts. In a preferred mode, the amlodipine base purified by the methods of the present invention is reacted with a pharmaceutically acceptable acid to form an amlodipine salt expressing the desired degree of purity, e.g. pharmaceutical purity without further purification.

Amlodipinske soli lahko pripravimo npr. z obdelavo raztopine ali suspenzije amlodipinske baze v ustreznem topilu z ekvivalentno količino kisline in izolacijo nastale soli iz reakcijske zmesi. Amlodipinske soli, ki se jih da pripraviti s to metodo, prednostno vključujejo, toda nanje niso omejene, soli s farmacevtsko sprejemljivimi kislinami; primeri so amlodipin maleat, fumarat, hidrogen maleat, bezilat, bezilat monohidrat, bezilat dihidrat, hidroklorid, mezilat, mezilat monohidrat, hidrobromid, citrat in tartrat.Amlodipine salts can be prepared e.g. by treating an amlodipine base solution or suspension in a suitable solvent with an equivalent amount of acid and isolating the resulting salt from the reaction mixture. The amlodipine salts which can be prepared by this method preferably include, but are not limited to, salts with pharmaceutically acceptable acids; examples are amlodipine maleate, fumarate, hydrogen maleate, besylate, besylate monohydrate, besylate dihydrate, hydrochloride, mesylate, mesylate monohydrate, hydrobromide, citrate and tartrate.

Ustrezen postopek za izdelavo tablete proste baze amlodipina lahko obsega kakršenkoli konvencionalni postopek. Sestavke tega izuma lahko formuliramo s konvencionalnimi metodami pomešanja, kot je mešanje, polnjenje in stiskanje s pomočjo mokre granulacije, suhe granulacije ali neposredega stiskanja. Zadnji postopek je najbolj ugoden in prednosten in ga lahko uporabimo za tabletni sestavek v smislu izuma v industrijskem merilu.A suitable process for making a free base tablet of amlodipine may comprise any conventional method. The compositions of the present invention can be formulated by conventional blending methods such as mixing, filling and pressing by wet granulation, dry granulation or direct compression. The latter process is most advantageous and preferred and can be used for a tablet composition of the invention on an industrial scale.

Medtem ko je predloženi izum primarno usmerjen k tabletam, lahko iz proste baze amlodipina pripravimo tudi kapsulsko dozirno obliko. Kapsulski sestavki lahkoWhile the present invention is primarily tablet-based, a capsule dosage form can also be prepared from the free base of amlodipine. Capsule compositions may

-1313 obsegajo v bistvu enake ekscipiente kot tabletni sestavki. Ugoden inertni nosilec je mikrokristalna celuloza brez kalcijevega fosfata.-1313 comprise essentially the same excipients as the tablet compositions. A favorable inert carrier is microcrystalline cellulose without calcium phosphate.

Prosto bazo amlodipina lahko uporabimo tudi v medicinskih aplikacijah v kombinaciji z drugimi antihipertenzijskimi in/ali antianginalnimi sredstvi, npr. z ACE-inhibitorji, kot je benazepril. Kombinacije so lahko v obliki enojnega kombiniranega pripravka, npr. kapsule, ki vsebuje prosto bazo amlodipina in benazepril hidroklorid, ali pa z ločenim dajanjem zdravil, ki vsebujejo gornja sredstva. Prosto bazo amlodipina lahko uporabimo tudi v kombinaciji z različnimi sredstvi, ki znižujejo holesterol, kot je lovastatin, simvastatin ali atorvastatin.The free base of amlodipine can also be used in medical applications in combination with other antihypertensive and / or antianginal agents, e.g. with ACE inhibitors such as benazepril. The combinations may take the form of a single combination preparation, e.g. capsules containing the free base of amlodipine and benazepril hydrochloride, or by the separate administration of medicines containing the above agents. The free base of amlodipine can also be used in combination with various cholesterol lowering agents such as lovastatin, simvastatin or atorvastatin.

Prosto bazo amlodipina lahko uporabimo pri obravnavanju naslednjih motenj: hipertenzije kronične stabilne angine pectoris vazospastične angine (Prinzmetalove angine) kongestivne odpovedi srca.The free base of amlodipine can be used to address the following disorders: hypertension of chronic stable angina pectoris vasospastic angina (Prinzmetal angina) congestive heart failure.

Te motnje so tu dalje navedene kot Motnje. Torej predloženi izum nadalje zagotavlja postopek za zdravljenje in/ali preprečevanje katerekoli ali večih Motenj z dajanjem učinkovite in/ali profilaktične količine proste baze amlodipina znotraj sestavka v smislu izuma, pacientu, ki jo potrebuje. Učinkovita količina je znana v stroki. Npr. pri ljudeh je učinkovita količina značilno med 1 in 100 mg proste baze amlodipina. Enotska doza, kot je opisana predhodno, se normalno jemlje od 1 do 3-krat dnevno prednostno 1-krat dnevno. V praksi bo zdravnik določil aktualno dozo in režim dajanja, ki bo najbolj ustrezen za posameznega pacienta.These disorders are hereinafter referred to as Disorders. Thus, the present invention further provides a method of treating and / or preventing any or more of the Disorders by administering to the patient in need thereof an effective and / or prophylactic amount of the free base of amlodipine within the composition of the invention. An effective amount is known in the art. E.g. in humans, the effective amount is typically between 1 and 100 mg of the free base of amlodipine. A single dose, as described previously, is normally taken 1 to 3 times daily, preferably 1 time daily. In practice, the doctor will determine the current dose and dosage regimen most appropriate for the individual patient.

Predloženi izum zagotavlja tudi uporabo sestavka v smislu izuma v izdelavi zdravila za zdravljenje in/ali preprečevanje katerekoli ali večih izmed Motenj.The present invention also provides the use of a composition of the invention in the manufacture of a medicament for the treatment and / or prevention of any or more of the Disorders.

Naslednji primeri ponazarjajo izum, toda ne gre jih smatrati, kot da omejujejo izum.The following examples illustrate the invention but should not be construed as limiting the invention.

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Referenčni primer 1, ki temelji na McDaid-u in Deasy-uReference Case 1 based on McDaid and Deasy

1,15 g 250 ml 1.15 g 250 ml amlodipin bezilata smo raztopili v vode pri 50 °C-55 °C. Dodali smo amlodipine besylate was dissolved in of water at 50 ° C-55 ° C. We added 2,2 ml 2.2 ml 1 M NaOH raztopine. Zmes smo naravnali na 3°C-5°C in jo mešali pri tej temperaturi 1 uro. Trdno snov smo odfiltrirali in sprali z 1 M NaOH solution. The mixture was adjusted to 3 ° C-5 ° C and stirred at this temperature for 1 hour. The solid was filtered off and washed with 2*5 ml 2 * 5 ml vode in posušili v vakuumski peči. Dobili smo of water and dried in a vacuum oven. We got 0,73 g Dobitek: 0.73 g Yield: trdne snovi. 0,73 g (88 %) solids. 0.73 g (88%) NMR: NMR: ustreza prosti bazi amlodipina corresponds to the free base of amlodipine DSC: DSC: ustreza prosti bazi amlodipina oblika I corresponds to the free base of amlodipine form I

Referenčni primer 2, ki temelji na McDaid-u in Deasy-uReference Case 2 based on McDaid and Deasy

1,5 g 30 ml 1.5 g 30 ml amlodipin bezilata smo raztopili v metanola. Dodali smo amlodipine besylate was dissolved in methanol. We added 3,1 ml 40 ml 3.1 ml 40 ml 1 M NaOH dodali smo dietil etra. Opazili nismo ločevanja plasti. Dodali smo 1 M NaOH was added diethyl ether. No layer separation was observed. We added 10 ml 10 ml vode. Plasti so se ločile in organsko plast smo posušili nad Na₂SO₄. Zmes smo uparili do suhega in tako dobljeno trdno snov posušili v vakuumski peči. Dobili smowater. The layers separated and the organic layer was dried over Na ₂ SO ₄ . The mixture was evaporated to dryness and the solid thus obtained was dried in a vacuum oven. We got 0,85 g Dobitek: 0.85 g Yield: trdne snovi. 0,85 g (78 %) solids. 0.85 g (78%) NMR: NMR: ustreza prosti bazi amlodipina corresponds to the free base of amlodipine DSC: DSC: ustreza prosti bazi amlodipina oblika I corresponds to the free base of amlodipine form I

Referenčni primer 3Reference case 3

6 kg 121 6 kg 121 amlodipin bezilata smo suspendirali v 2-propanola. Pri 200 RPM (obr./min.) smo mešali 15 minut. Dodali smo we suspended amlodipine besylate v 2-propanol. At 200 RPM (rpm), it was stirred for 15 minutes. We added 10,61 10,61 NaOH 1 M v vodi. Opazili nismo eksotermnega učinka. Mešali smo NaOH 1 M in water. No exothermic effect was observed. We were mixing 201 201 pri 200 RPM (obr./min.) 1 uro. Dodali smo vode v 10 minutah, dodali smo kalilne kristale. Dodali smo at 200 RPM (rpm) for 1 hour. We added of water in 10 minutes, germination crystals were added. We added 41 41 vode, opazili majhen eksotermen učinek zaradi kristalizacije. Hitrost mešanja smo naravnali na 150 RPM (obr./min) in mešali 1 uro pri water, a small exothermic effect due to crystallization was observed. Speed The stirring was adjusted to 150 RPM (rpm) and stirred for 1 hour at

-1515-1515

20 °C. Reakcijsko zmes smo ohladili do 5 °C v 2 urah in mešali pri 5 °C 30 minut. Trdno snov smo odfiltrirali in sprali z 25 ° C. The reaction mixture was cooled to 5 ° C for 2 hours and stirred at 5 ° C for 30 minutes. The solid was filtered off and washed with 2*5 1 2 * 5 1 vode. Trdno snov smo sušili v vakuumski peči pri 40 °C 4 dni. water. The solid was dried in a vacuum oven at 40 ° C for 4 days. Dobitek: Yield: 4,05 kg (93,5 %) rahlo rumenih kristalov, povprečna velikost delcev okoli 230 mikrometrov. 4.05 kg (93.5%) of slightly yellow crystals, average particle size about 230 micrometers. čistota: purity: 99,7 % 99.7% NMR: NMR: ustreza prosti bazi amlodipina corresponds to the free base of amlodipine DSC in IR DSC and IR sta pokazala obliko I showed Form I XRPD XRPD je prikazan na sl. 1. is shown in FIG. 1.

Primer 1 Sinteza proste baze amlodipinaExample 1 Synthesis of the free base of amlodipine

250 ml 250 ml 40 %-nega metilamina v vodi in Of 40% methylamine in water and 31,5 g 460 ml 31.5 g 460 ml ftalodipina smo mešali pri 40 °C-45 °C 16 ur. Dodali smo toluena in zmes mešali 30 minut. Plasti so se ločile in organsko plast smo sprali s phthalodipine was stirred at 40 ° C-45 ° C for 16 hours. Toluene was added and the mixture was stirred for 30 minutes. The layers separated and the organic layer we washed with 150 ml 150 ml vode. Plasti so se ločile in organsko plast smo uparili do suhega. Dobljeno trdno snov smo posušili pri 40 °C v vakuumski peči. Dobili smo water. The layers separated and the organic layer was evaporated to dryness. The resulting solid was dried at 40 ° C in a vacuum oven. Got it we are 21,6 g Dobitek: 21.6 g Yield: trdne snovi. 21,6 g (92 %) solids. 21.6 g (92%) HPLC: HPLC: 98,8 površinskih % 98.8 surface% Tal.: Tal .: 136 °C-139 °C (nepopravljeno) 136 ° C-139 ° C (uncorrected) IR: IR: ustreza obliki I kot je prikazana na sl. 2 corresponds to Form I as shown in FIG. 2 DSC: DSC: ustreza obliki I kot je prikazana na sl. 3. corresponds to Form I as shown in FIG. 3.

Primer 2 Sinteza proste baze amlodipina 100 ml 40 % metilamina v vodi inExample 2 Synthesis of free base amlodipine 100 ml 40% methylamine in water and

12,6 g 150 ml 12.6 g 150 ml ftalodipina smo mešali pri 40°C-45°C 16 ur. Dodali smo toluena in zmes mešali 30 minut. Plasti so se ločile in organsko plast smo sprali s phthalodipine was stirred at 40 ° C-45 ° C for 16 hours. Toluene was added and the mixture was stirred for 30 minutes. The layers separated and the organic layer we washed with 50 ml 50 ml vode. Zmes smo zmanjšali do približno 20 ml in ohladili ob mešanju na ledeni kopeli. Začela seje obarjati trdna snov, katero smo odfiltri- water. The mixture was reduced to about 20 ml and cooled with stirring on an ice bath. The solids, which were filtered off, began to precipitate.

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rali in sprali s rally and wash with 5 ml 5 ml toluena. Trden produkt smo posušili v vakuumski peči. toluene. The solid product was dried in a vacuum oven. HPLC: HPLC: 98,8 površinskih % 98.8 surface% NMR: NMR: ustreza amlodipinski bazi corresponds to the amlodipine base DSC: DSC: ustreza amlodipinski bazi oblika I corresponds to the form I amlodipine base

Primer 3 Sinteza proste baze amlodipina 100 ml 40 % metilamina v vodi inExample 3 Synthesis of free base of amlodipine 100 ml of 40% methylamine in water and

12,6 g 12.6 g ftalodipina smo mešali pri 40 °C-45 °C 16 ur. Zmes smo filtrirali in dobljeno trdno snov smo sprali z phthalodipine was stirred at 40 ° C-45 ° C for 16 hours. The mixture was filtered and the resulting solid was washed with 2x10 ml 2x10 ml vode. Trdno snov smo posušili v vakuumski peči. water. The solid was dried in a vacuum oven. Dobitek: Yield: 6 g (64 %) 6 g (64%) HPLC: HPLC: 98,8 površinskih % 98.8 surface% NMR: NMR: ustreza amlodipinski bazi corresponds to the amlodipine base DSC: DSC: ustreza amlodipinski bazi oblika I. corresponds to amlodipine form I.

Primer 4a Kristalizacija amlodipinske baze za tvorbo oblike IExample 4a Crystallization of the Amlodipine Form I Formation Base

6,5 g surove proste baze amlodipina iz primera 1 smo raztopili v6.5 g of the crude free base of amlodipine from Example 1 were dissolved in

60 ml 60 ml vrelega etanola. Dodali smo of boiling ethanol. We added 120 ml 120 ml vode in zmes pustili, da seje ohladila do sobne temperature. Med ohlajanjem seje začela obarjati trdna snov. Zmes smo ohlajali na ledeni kopeli 1 uro. Trdno snov smo odfiltrirali in sprali z of water and the mixture was allowed to cool to room temperature. As the session cooled, the solid began to precipitate. The mixture was cooled in an ice bath for 1 hour. The solid was filtered off and washed with 10 ml 10 ml vode. Trdno snov smo posušili v vakuumski peči pri 40 °C. Dobili smo water. The solid was dried in a vacuum oven at 40 ° C. We got 5,8 g Dobitek: 5.8 g Yield: trdne snovi. 5,8 g (89%) solids. 5.8 g (89%) HPLC: HPLC: 99,3 površinskih % 99.3 surface% Tal.: Tal .: 140°C-141°C (nepopravljeno) 140 ° C-141 ° C (uncorrected) IR: IR: ustreza obliki I, kot je prikazana na sl. 4 corresponds to Form I as shown in FIG. 4 DSC: DSC: ustreza obliki I, kot je prikazana na sl. 5. corresponds to Form I as shown in FIG. 5.

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Primer 4b Example 4b 2,0 g 5 ml 2,0 g 5 ml proste baze amlodipina smo raztopili v etilacetata ob segrevanju pri refluksu in filtrirali preko hyflo, da smo dobili bistro raztopino. To toplo raztopino smo po kapljicah dodali k amlodipine free bases were dissolved in of ethyl acetate under reflux and filtered over hyflo to give a clear solution. This warm solution was added dropwise 100 ml 100 ml heptana ob močnem mešanju. Iz zmesi seje oboril amlodipin in izolirali smo ga s filtracijo. Kristale (fin prah) smo posušili v vakuumu pri sobni temperaturi. of heptane with vigorous stirring. Amlodipine precipitated from the mixture of the session and was isolated by filtration. The crystals (fine powder) were dried in vacuo at room temperature.

Primer 5a Kristalizacija amlodipinske baze za tvorbo oblike IIExample 5a Crystallization of Amlodipine Form II Formation Base

6,5 g 25 ml 6.5 g 25 ml proste baze amlodipina iz primera 1 smo raztopili v vrelega toluena. To zmes smo počasi, v 15 minutah, ob mešanju dodali k0°C-3°C the free bases of amlodipine from Example 1 were dissolved in of boiling toluene. This mixture was added slowly over 15 minutes with stirring k0 ° C-3 ° C 300 ml 300 ml raztopine N-heksana. Med dodajanjem smo temperaturo raztopine N-heksana vzdrževali pod 3 °C. Trdno snov smo odfiltrirali in posušili of N-hexane solution. During the addition, the temperature of the N-hexane solution was maintained below 3 ° C. The solid was filtered off and dried 6,0 g Dobitek: 6,0 g Yield: pod vakuumom pri sobni temperaturi. Dobili smo bele trdne snovi. 6,0 g (92%) under vacuum at room temperature. We got white solids. 6.0 g (92%) HPLC: HPLC: 99,3 površinskih % 99.3 surface% IR: IR: ustreza obliki II, kot je prikazana na sl. 6. corresponds to Form II as shown in FIG. 6. Tal.: Tal .: 138°C-140°C (nepopravljeno) 138 ° C-140 ° C (uncorrected) DSC: DSC: 100,12°C začetek in 140,39°C začetek kot je prikazan na sl. 7. 100.12 ° C onset and 140.39 ° C onset as shown in FIG. 7.

Primer 5b Example 5b 5,0 g 10 ml 5.0 g 10 ml proste baze amlodipina smo raztopili v etilacetata ob segrevanju pri refluksu. Takoj nato, ko smo dobili bistro raztopino, smo vročo zmes prisilili, da seje ohladila do -78 °C (suh led/aceton). Kristalizacija se ni pojavila. Vendar pa se je izven kopeli s suhim ledom nenadoma raztopina strdila. Kristale (v obliki prahu) smo izolirali s filtracijo in posušili v vakuumu pri sobni temperaturi. amlodipine free bases were dissolved in of ethyl acetate at reflux. Immediately after clear solution was obtained, the hot mixture was forced to cool to -78 ° C (dry ice / acetone). Crystallization did not occur. However, outside the dry ice bath, the solution suddenly solidified. The crystals (in powder form) were isolated by filtration and dried in vacuo at room temperature. IR: IR: ustreza obliki II conforms to Form II

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Primer 5 c Example 5 c 2,0 g 6 ml 2,0 g 6 ml proste baze amlodipina smo raztopili v etilacetata ob segrevanju pri refluksu. Vročo raztopino smo filtrirali amlodipine free bases were dissolved in of ethyl acetate at reflux. The hot solution was filtered 100 ml 100 ml skozi hyflo, da smo dobili bistro raztopino in jo po kapljicah dodali k heptana ob močnem mešanju pri -78 °C. Temperaturo heptanske plasti smo vzdrževali pod -70 °C. Oborino smo zbrali s filtracijo in jo sušili preko noči pod vakuumom pri sobni temperaturi. through hyflo to give a clear solution and dropwise added to heptane with vigorous stirring at -78 ° C. The temperature of the heptane layer was maintained below -70 ° C. The precipitate was collected by filtration and dried overnight under vacuum at room temperature.

IR: ustreza obliki IIIR: Corresponds to Form II

Primer 5 d Example 5 d 2,5 g 7 ml 2.5 g 7 ml proste baze amlodipina smo raztopili v etilacetata ob segrevanju pri refluksu. Vročo raztopino smo filtrirali amlodipine free bases were dissolved in of ethyl acetate at reflux. The hot solution was filtered 100 ml 100 ml skozi hyflo in po kapljicah dodali k na ledu ohlajeni (0 °C) plasti heptana ob močnem mešanju. Temperaturo heptanske plasti smo vzdrževali med 0-1 °C. Oborino smo izolirali s filtracijo in jo preko through hefl and dropwise added to the ice-cooled (0 ° C) layers of heptane with vigorous stirring. The temperature of the heptane layer was maintained between 0-1 ° C. The precipitate was isolated by filtration and filtered over IR: IR: noči sušili pod vakuumom pri sobni temperaturi. ustreza obliki II. nights were dried in vacuo at room temperature. conforms to Form II.

Primer 5e Example 5e 2,0 g 10 ml 2,0 g 10 ml proste baze amlodipina smo raztopili v toluena ob segrevanju pri refluksu. Vročo raztopino smo filtrirali amlodipine free bases were dissolved in of toluene upon reflux heating. The hot solution was filtered 100 ml 100 ml skozi hyflo in po kapljicah dodali k predhodno ohlajeni (0 °C) plasti heptana ob močnem mešanju. Temperaturo heptanske plasti smo vzdrževali med 0-1 °C. Oborino smo izolirali s filtriranjem in jo through hyflo and dropwise added to the pre-cooled (0 ° C) layer of heptane with vigorous stirring. The temperature of the heptane layer was maintained between 0-1 ° C. The precipitate was isolated by filtration and filtered IR: IR: sušili preko noči pod vakuumom pri sobni temperaturi. ustreza obliki II. dried overnight under vacuum at room temperature. conforms to Form II.

Primer 6a Sinteza proste baze amlodipina oblike II 100 ml 40 % metilamina v vodi inExample 6a Synthesis of free base amlodipine Form II 100 ml of 40% methylamine in water and

12,6 g 150 ml 12.6 g 150 ml ftalodipina smo mešali pri 40 °C-45 °C 16 ur. Dodali smo toluena in zmes mešali 30 minut. Plasti so se ločile in organsko plast phthalodipine was stirred at 40 ° C-45 ° C for 16 hours. We added toluene and the mixture were stirred for 30 minutes. The layers separated and the organic layer

-1919 smo sprali s-1919 we washed with

50 ml 50 ml vode. Zmes smo zmanjšali do približno 75 ml in ohladili na kopeli led-sol do približno -10 °C. Tvorila seje trdna snov, ki smo jo odfiltrirali in sprali s water. The mixture was reduced to about 75 ml and cooled in an ice-salt bath to about -10 ° C. It formed the solid that we are filtered and washed with 5 ml 5 ml toluena. Trden produkt smo posušili v vakuumski peči. toluene. The solid product was dried in a vacuum oven. Dobitek: Yield: 8,6 g (92%) 8.6 g (92%) HPLC: HPLC: (98,8 površinskih %) (98.8 surface%) NMR: NMR: ustreza prosti bazi amlodipina corresponds to the free base of amlodipine DSC: DSC: ustreza amlodipinski bazi oblika II. corresponds to amlodipine form II base. Primer 6b Sinteza proste baze amlodipina oblika II Example 6b Synthesis of free base amlodipine form II 100 ml 100 ml 40 % metilamina v vodi in 40% methylamine in water and 12,6 g 12.6 g ftalodipina FB.ADP.010710.01 smo mešali pri 40 °C-45 °C 16 ur. Dodali smo phthalodipine FB.ADP.010710.01 was stirred at 40 ° C-45 ° C for 16 hours. We added 150 ml 150 ml toluena in zmes mešali 30 minut. Plasti so se ločile in organsko plast smo sprali s toluene and the mixture were stirred for 30 minutes. The layers separated and the organic layer we washed with 50 ml 50 ml vode. Organsko plast smo zmanjšali do 75 ml in ohladili do -20 °C. Dodali smo water. The organic layer was reduced to 75 ml and cooled to -20 ° C. We added 75 ml 75 ml n-heptana. Začela se je obarjati trdna snov, katero smo odfiltrirali. Trdno snov smo sprali z of n-heptane. A solid began to precipitate, which was filtered off. The solid was washed with 2*5 ml 2 * 5 ml n-heptana in jo posušili v vakuumski peči. Dobili smo n-heptane and dried in a vacuum oven. We got 7,9 g 7,9 g trdne snovi. solids. Dobitek: Yield: 7,9 g (85%) 7.9 g (85%) HPLC: HPLC: (98,8 površinskih %) (98.8 surface%) NMR: NMR: ustreza prosti bazi amlodipina corresponds to the free base of amlodipine IR: IR: ustreza obliki II conforms to Form II DSC: DSC: ustreza obliki II conforms to Form II

Primer 7 Konverzija amlodipinske baze oblike II v obliko I g amlodipinske baze II smo segrevali 115 °C 4 ure. Raztopina je postala rumena. Dobili smo 0,9 g trdne snoviExample 7 The conversion of amlodipine base Form II to Form I g amlodipine base II was heated at 115 ° C for 4 hours. The solution turned yellow. 0.9 g of a solid was obtained

IR: ustreza prosti bazi amlodipinaIR: corresponds to the free base of amlodipine

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DSC: ustreza obliki IDSC: Corresponds to Form I

Primer 8 Čiščenje amlodipinske baze preko soliExample 8 Purification of the Amlodipine Base via Salt

2,3 g surove amlodipinske baze smo raztopili v2.3 g of crude amlodipine base were dissolved in

50 ml 50 ml toluena. Dodali smo toluene. We added 150 ml 150 ml 0,05 M raztopine HCI in zmes močno stresali. Plasti so se ločile in k 0.05 M HCl solution and the mixture was shaken vigorously. The layers separated and k 10 ml 10 ml vodni plasti smo dodali IM NaOH raztopine. Začela seje tvoriti trdna snov in zmes smo mešali 45 minut pri 3 °C-5 °C. Trdno snov smo odfiltrirali in sprali water layers were added IM NaOH solutions. The solids began to form and the mixture was stirred for 45 minutes at 3 ° C-5 ° C. The solid was filtered off and washed 2x5 ml 2x5 ml Z vode. Trdno snov smo posušili v vakuumski peči. Dobili smo Z water. The solid was dried in a vacuum oven. We got 1,65 g Dobitek: 1.65 g Yield: trdne snovi. 1,65 g (72%) solids. 1.65 g (72%) NMR: NMR: ustreza amlodipinski bazi corresponds to the amlodipine base DSC: DSC: ustreza amlodipinski bazi oblika I corresponds to the form I amlodipine base

Primer 9 Primerjava lepljivostiExample 9 Comparison of stickiness

Na EKO ekscentrični stiskalnici (Korsch) smo izdelali tablete z naslednjo sestavoAt EKO eccentric press (Korsch) we made tablets with the following composition

Tablete amlodipin bezilataAmlodipine bezilate tablets

47,5 % 47,5 % 5,0 % 47,5% 47,5% 5.0% mikrokristalne celuloze (Avicell PH 112; FMC) kalcijevega sulfata dihidrata (Compactrol, Penwest Pharmaceuticals Co) amlodipin bezilata microcrystalline cellulose (Avicell PH 112; FMC) calcium sulphate dihydrate (Compactrol, Penwest Pharmaceuticals Co) amlodipine besylate

Tablete proste baze amlodipinaAmlodipine free base tablets

48,2 % 48,2 % 3,67 % 48,2% 48,2% 3.67% mikrokristalne celuloze (Avicell PH 112; FMC) kalcijevega sulfata dihidrata (Compactrol; Penwest Pharmaceuticals Co) amlodipinske baze (Ref. prim. 3) microcrystalline cellulose (Avicell PH 112; FMC) calcium sulphate dihydrate (Compactrol; Penwest Pharmaceuticals Co) amlodipine base (Ref. cf. 3)

Lastnosti tablet:Tablet features:

premer izsekovalnika : 20 mmpuncher diameter: 20 mm

teža tablete: tablet weight: 400 mg 400 mg

-2121 trdota: približno 200 N-2121 Hardness: about 200 N

Po 50 tabletah smo iz izsekovalnikov ekstrahirali tabletni material z uporabo metanola in ultrazvočne kopeli. Ta postopek smo ponovili za serije 100, 150, 200, 250 in 300 tablet. Ekstrakte smo skupaj z kalibracijskimi vzorci amlodipina merili spektrometrično. Količino amlodipina v vzorcih smo izračunali iz kalibracijske krivulje in celokupno količino amlodipina, ekstahiranega iz obeh, gornjega in spodnjega izsekovalnika, smo izrisali proti količini izdelanih tablet. Povprečno vrednost za lepljivost smo izračunali iz naklona regresij ske premice s premikom yodseka premice skozi nič.After 50 tablets, tablet material was extracted from the punchers using methanol and an ultrasonic bath. This procedure was repeated for batches of 100, 150, 200, 250 and 300 tablets. The extracts, together with the calibration samples of amlodipine, were measured spectrometrically. The amount of amlodipine in the samples was calculated from the calibration curve and the total amount of amlodipine extracted from both the upper and lower punctures was plotted against the amount of tablets produced. The average value for stickiness was calculated from the slope of the regression line by moving the yodseka of the line through zero.

Povprečni ostanek (lepljivost) amlodipinske baze: 0,55 pg ADP.cm'².tableta'¹ Average residue (stickiness) of amlodipine base: 0.55 pg ADP.cm ' ² .tablets' ¹

Povprečni ostanek (lepljivost) amlodipin bezilata; 1,16 pg ADP.cm'².tableta’¹ Mean residue (stickiness) of amlodipine besylate; 1.16 pg ADP.cm ' ² .tablets' ¹

Primer 10 Farmacevtska tableta, ki obsega prosto bazo amlodipinaExample 10 A pharmaceutical tablet comprising the free base of amlodipine

a) Tabletni sestavek z kalcijevim hidrogen fosfatom/mikrokristalno celulozoa) Calcium hydrogen phosphate / microcrystalline cellulose tablet composition

Številka šarže Batch number A A B B C C D D E E F F amlodipinska baza (iz ref.prim. 3) amlodipine base (from ref. 3) 2,5 mg 2.5 mg 10 mg 10 mg 2,5 mg 2.5 mg 10 mg 10 mg amlodipinska baza mleta (iz ref. prim. 3) amlodipine ground base (from ref. cf. 3) 2,5 mg 2.5 mg 10 mg 10 mg kalcijev hidrogen fosfat brezvodni calcium hydrogen phosphate anhydrous 31,5 mg 31.5 mg 126,0 mg 126.0 mg 31,5 mg 31.5 mg 126,0 mg 126.0 mg 31,5 mg 31.5 mg 126.0 mg 126.0 mg mikrokristalna celuloza microcrystalline cellulose 62,05 mg 62.05 mg 248,1 mg 248,1 mg 62,05 mg 62.05 mg 248,1 mg 248,1 mg 62,05 mg 62.05 mg 248,1 mg 248,1 mg natrijev škrobni glikolat sodium starch glycolate 2,0 mg 2.0 mg 8.0 mg 8.0 mg 2,0 mg 2.0 mg 8,0 mg 8.0 mg 2,0 mg 2.0 mg 8,0 mg 8.0 mg

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magnezijev stearat magnesium stearate 1,0 mg 1.0 mg 4,0 mg 4.0 mg 1,0 mg 1.0 mg 4,0 mg 4.0 mg 1,0 mg 1.0 mg 4,0 mg 4.0 mg celokupno overall 99,05 mg 99.05 mg 396,1 mg 396.1 mg 99,05 mg 99.05 mg 396,1 mg 396.1 mg 99,05 mg 99.05 mg 396,1 mg 396.1 mg

Šarže amlodipinske baze A, B, E in F smo izdelali kot sledi:The batches of amlodipine base A, B, E and F were made as follows:

Amlodipinsko bazo smo presejali skozi 500 pm sito.The Amlodipine base was sieved through a 500 pm sieve.

Druge ekscipiente smo presejali skozi 850 pm sito.Other excipients were screened through a 850 pm sieve.

Vse ekscipiente, razen magnezijevega stearata, smo mešali v mešalniku s prostim padom 15 minut pri okoli 25 obr./min.All excipients except magnesium stearate were stirred in a free-fall mixer for 15 minutes at about 25 rpm.

Dodali smo magnezijev stearat in praškasto mešanico mešali še nadaljnjih 5 minut pri okoli 25 obr./min.Magnesium stearate was added and the powder mixture was stirred for a further 5 minutes at about 25 rpm.

2,5 mg in 10 mg tablete smo stisnili z uporabo Korsch EKO ekscentrične stiskalnice.2.5 mg and 10 mg tablets were compressed using a Korsch EKO eccentric press.

Šarži amlodipina C in D smo izdelali kot sledi.Amlodipine C and D batches were manufactured as follows.

Amlodipinsko bazo smo zmleli.We ground the Amlodipine base.

Dodali smo magnezijev stearat in praškasto mešanico mešali nadaljnjih 5 minut pri okoli 25 obr./min.Magnesium stearate was added and the powder mixture was stirred for a further 5 minutes at about 25 rpm.

Pri proizvodnji gornjih tablet nismo naleteli na nobene probleme.We did not encounter any problems in the manufacture of the above tablets.

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b) Tabletni sestavek, ki temelji na mikrokristalni celulozi.b) Tablet composition based on microcrystalline cellulose.

Številka šarže Batch number G Mr H H amlodipinska baza (iz ref. prim. 3) amlodipine base (from ref. cf. 3) 2,5 mg 2.5 mg 10 mg 10 mg mikrokristalna celuloza microcrystalline cellulose 75,55 mg 75.55 mg 302,1 mg 302,1 mg predsušen krompirjev škrob dried potato starch 20,0 mg 20,0 mg 80,0 mg 80,0 mg magnezijev stearat magnesium stearate 0,5 mg 0.5 mg 2,0 mg 2.0 mg smukec talc 0,5 mg 0.5 mg 2,0 mg 2.0 mg celokupno overall 99,05 mg 99.05 mg 396,1 mg 396.1 mg

Postopek izdelave:Manufacturing process:

Amlodipinsko bazo smo presejali skozi 500 μιη sito.The Amlodipine base was screened through a 500 μιη sieve.

Druge ekscipiente smo presejali skozi 850 μιη sito.Other excipients were screened through a 850 μιη sieve.

Vse ekscipiente, razen magnezijevega stearata in smukca, smo mešali v mešalniku s prostim padom 15 minut pri okoli 25 obr./min.All excipients except magnesium stearate and talc were mixed in a free-fall mixer for 15 minutes at about 25 rpm.

Dodali smo magnezijev stearat in smukec in praškasto zmes mešali še nadaljnjih 5 minut pri okoli 25 obr./min.Magnesium stearate was added and talc and the powder mixture was stirred for a further 5 minutes at about 25 rpm.

c)c)

Profile raztapljanja smo posneli z uporabo aparature z lopatico pri hitrosti vrtenja 75 obr./min in mediju raztapljanja 500 ml 0,01 M klorovodikovi kislini. Vzorce raztapljanja smo analizirali z UV spektrofotometrijo pri 237 nm. Povprečne vrednosti raztapljanja (v % navedene količine) so predstavljene v tabeli.The dissolution profiles were recorded using a spatula apparatus at a speed of 75 rpm and a dissolution medium of 500 ml of 0.01 M hydrochloric acid. The dissolution samples were analyzed by UV spectrophotometry at 237 nm. The average dissolution values (in% of the quantity indicated) are presented in the table.

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v Sarža v Sarzha 0 min 0 min 3 min 3 min 6 min 6 min 9 min 9 min 12 min 12 min 15 min 15 min 20 min 20 min 30 min 30 min 45 min 45 min 60 min 60 min A A 0 0 83 83 93 93 96 96 97 97 97 97 97 97 97 97 98 98 98 98 B B 0 0 89 89 97 97 99 99 101 101 101 101 102 102 102 102 103 103 103 103 G Mr 0 0 92 92 97 97 98 98 98 98 98 98 99 99 99 99 100 100 100 100 H H 0 0 86 86 91 91 94 94 95 95 96 96 97 97 99 99 101 101 102 102 C C 0 0 88 88 95 95 96 96 97 97 97 97 98 98 98 98 98 98 98 98 D D 0 0 86 86 94 94 96 96 97 97 97 97 98 98 99 99 100 100 100 100

Primer 11 Kapsule proste baze amlodipinaExample 11 Amlodipine free base capsules

Sestava:Composition:

00E29/1 00E29 / 1 amlodipinska baza amlodipine base 5,0 mg 5.0 mg mikrokristalna celuloza microcrystalline cellulose 72,6 mg 72,6 mg predsušen krompirjev škrob dried potato starch 20,0 mg 20,0 mg magnezijev stearat magnesium stearate 0,5 mg 0.5 mg celokupno overall 98,1 mg 98.1 mg

Postopek:Process:

Zelatinske kapsule smo napolnili s to praškasto mešanico.The capsule capsules were filled with this powder mixture.

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Izum smo opisali, toda strokovnjakom s področja bodo zlahka očitne nadaljnje spremembe in modifikacije v dejanski izvedbi konceptov in tukaj opisane izvedbe se zlahka izvedejo ali pa se jih da naučiti s prakso tega izuma, ne da bi zapustili duh in obseg izuma, kot je definiran z naslednjimi zahtevki.The invention has been described, but it will be readily apparent to those skilled in the art that further modifications and modifications will be made to the actual implementation of the concepts and the embodiments described herein will be readily made or taught by the practice of the present invention without leaving the spirit and scope of the invention as defined by the following claims.

Claims

1. Farmacevtski tabletni sestavek, ki obsega učinkovito količino proste baze amlodipina in vsaj en farmacevtsko sprejemljiv ekscipient, označen s tem, da navedena tableta izraža nizek izsekovalni ostanek.A pharmaceutical tablet composition comprising an effective amount of amlodipine free base and at least one pharmaceutically acceptable excipient, characterized in that said tablet expresses a low excisional residue.

2. Sestavek po zahtevku 1, označen s tem, da navedena tableta pusti povprečni ostanek na tabletnem izsekovalniku 0,7 pg.cm' na tableto ali manj.Composition according to claim 1, characterized in that said tablet leaves an average residue on the tablet puncher of 0.7 pg.cm 'per tablet or less.

3. Sestavek po zahtevkih 1 ali 2, označen s tem, daje navedeni ekscipient kalcijev fosfat.Composition according to claims 1 or 2, characterized in that said excipient is calcium phosphate.

4. Sestavek po kateremkoli od zahtevkov 1-3, označen s tem, da je navedeni ekscipient mikrokristalna celuloza.Composition according to any one of claims 1-3, characterized in that said excipient is microcrystalline cellulose.

5. Sestavek po zahtevku 3, označen s tem, da nadalje obsega mikrokristalno celulozo.Composition according to claim 3, further comprising microcrystalline cellulose.

6. Sestavek po zahtevku 5, označen s tem, da je kalcijev fosfat brezvodni kalcijev hidrogen fosfat.Composition according to claim 5, characterized in that calcium phosphate is anhydrous calcium hydrogen phosphate.

7. Sestavek po kateremkoli od predhodnih zahtevkov, označen s tem, da je navedena prosta baza amlodipina prosta baza amlodipina kristalne oblike II.Composition according to any one of the preceding claims, characterized in that said free base of amlodipine is a free base of amlodipine of crystalline form II.

8. Sestavek po kateremkoli od zahtevkov 1-6, označen s tem, da je prosta baza 'amlodipina amorfna prosta baza amlodipina.Composition according to any one of claims 1-6, characterized in that the free base of 'amlodipine is an amorphous free base of amlodipine.

9. Sestavek po kateremkoli od predhodnih zahtevkov 1-6, označen s tem, da je navedeni amlodipin zmes kristalne proste baze amlodipina oblike I in oblike II.Composition according to any one of the preceding claims 1-6, characterized in that said amlodipine is a mixture of crystalline free base of form I and form II amlodipine.

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10. Sestavek po kateremkoli od predhodnih zahtevkov, označen s tem, da navedena tableta vsebuje 1 do 100 mg navedene proste baze amlodipina.Composition according to any one of the preceding claims, characterized in that said tablet contains 1 to 100 mg of said free base of amlodipine.

11. Kristalna prosta baza amlodipina oblike II.11. Crystalline free base of form II amlodipine.

12. Uporaba učinkovite količine proste baze amlodipina za izdelavo zdravila za zdravljenje ali preprečevanje hipertenzije, angine ali kongestivne odpovedi srca.12. Use of an effective amount of amlodipine free base for the manufacture of a medicament for the treatment or prevention of hypertension, angina or congestive heart failure.

13. Postopek, označen s tem, da obsega:13. A process, characterized in that it comprises:

odstranitev zaščite N-zaščitenemu amlodipinu s sredstvom za odstranitev zaščite, da se tvori prosta baza amlodipina;deprotecting N-protected amlodipine with a deprotecting agent to form the free base of amlodipine;

obarjanje navedene proste baze amlodipina iz raztopine; in izoliranje navedene oborjene proste baze amlodipina v obliki trdnega stanja.precipitation of said free base of amlodipine from solution; and isolating said precipitated free base of amlodipine in solid form.

14. Postopek po zahtevku 13, označen s tem, da tvorimo navedeno raztopino z navedenim korakom odstranitve zaščite.Process according to claim 13, characterized in that said solution is formed with the said deprotection step.

15. Postopek po zahtevku 14, označen s tem, da navedena raztopina vsebuje vodo.Process according to claim 14, characterized in that said solution contains water.

16. Postopek po kateremkoli od zahtevkov 13-15, označen s tem, da je navedeni N-zaščiten amlodipin ftalodipin s formulo (2a):A method according to any one of claims 13-15, characterized in that said N-protected amlodipine phthalodipine of formula (2a):

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17. Postopek po zahtevku 16, označen s tem, daje navedeno sredstvo za odstranitev zaščite vodni metilamin.Process according to claim 16, characterized in that said deprotecting agent is aqueous methylamine.

18. Postopek po kateremkoli od predhodnih zahtevkov 13-17, označen s tem, da se navedeni korak odstranitve zaščite zgodi v vodni raztopini ali suspenziji.A method according to any one of the preceding claims 13-17, characterized in that said removal step of the protection occurs in an aqueous solution or suspension.

19. Postopek po zahtevku 18, ki nadalje obsega ekstrakcijo navedene proste baze amlodipina v topilu, ki se ne meša z vodo, da se tvori navedena raztopina.The method of claim 18, further comprising extracting said free base of amlodipine in a water-immiscible solvent to form said solution.

20. Postopek po zahtevku 19, označen s tem, daje navedeno topilo, ki se ne meša z vodo, toluen.A process according to claim 19, characterized in that said water-immiscible solvent is toluene.

21. Postopek po kateremkoli od zahtevkov 13-19, označen s tem, da je navedeno obarjanje korak kristalizacije.Process according to any one of claims 13-19, characterized in that said precipitation is a crystallization step.

22. Postopek po zahtevku 21, označen s tem, da navedena kristalizacija obsega ohlajanje navedene raztopine.Process according to claim 21, characterized in that said crystallization comprises the cooling of said solution.

23. Postopek po zahtevku 22, označen s tem, da navedena kristalizacija dodatno obsega upaijanje dela topila iz navedene raztopine.Process according to claim 22, characterized in that said crystallization additionally comprises the uptake of a portion of the solvent from said solution.

24. Postopek po kateremkoli od zahtevkov 21-23, označen s tem, da navedena kristalizacija obsega dodajanje kontra-topila k navedeni raztopini.A process according to any one of claims 21-23, characterized in that said crystallization involves the addition of a counter-solvent to said solution.

25. Postopek po kateremkoli od zahtevkov 21-24, označen s tem, da se navedena kristalizacija prične pri temperaturi nad 5 °C.Process according to any one of claims 21-24, characterized in that said crystallization begins at a temperature above 5 ° C.

26. Postopek po kateremkoli od zahtevkov 21-24, označen s tem, da se navedena kristalizacija prične pri temperaturi 5 °C ali manj in da navedena raztopina temelji na nevodnem topilu.A process according to any one of claims 21-24, characterized in that said crystallization begins at a temperature of 5 ° C or less and that said solution is based on a non-aqueous solvent.

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27. Postopek po kateremkoli od zahtevkov 13-26, označen s tem, da je navedena izolirana prosta baza amlodipina prosta baza amlodipina kristalne oblike I.A method according to any one of claims 13-26, characterized in that said isolated amlodipine free base is a crystalline Form I amlodipine free base.

28. Postopek po kateremkoli od zahtevkov 13-26, označen s tem, da je navedena izolirana prosta baza amlodipina prosta baza amlodipina kristalne oblike II.A method according to any one of claims 13-26, characterized in that said isolated free base of amlodipine is a free base of amlodipine of crystalline form II.

29. Postopek po kateremkoli od zahtevkov 13-28, označen s tem, da nadalje obsega raztapljanje navedene izolirane proste baze amlodipina v nevodnem čistilnem topilu in kristalizacijo navedene raztopljene proste baze iz navedenega čistilnega topila, da se tvori očiščena kristalna prosta baza amlodipina.A process according to any one of claims 13-28, further comprising dissolving said isolated amlodipine free base in a non-aqueous cleaning solvent and crystallizing said dissolved free base from said cleaning solvent to form a purified crystalline free base of amlodipine.

30. Postopek za čiščenje proste baze amlodipina, označen s tem, da obsega: kristalizacijo proste baze amlodipina iz nevodnega topila.30. A process for the purification of the free base of amlodipine, characterized in that it comprises: crystallization of the free base of amlodipine from a non-aqueous solvent.

31. Postopek po zahtevku 30, označen s tem, da navedena kristalizacija proizvede kristale proste baze amlodipina, ki imajo povprečno velikost delcev od 150 do 350 mikrometrov.31. The method of claim 30, wherein said crystallization produces free base crystals of amlodipine having an average particle size of from 150 to 350 micrometers.

32. Populacija proste baze amlodipina v obliki delcev, označena s tem, da ima povprečno velikost delcev vsaj 100 mikrometrov.32. A particulate free amlodipine population having an average particle size of at least 100 micrometers.

33. Populacija po zahtevku 32, označena s tem, da so navedeni delci kristali.The population of claim 32, wherein said particles are crystals.

34. Populacija po zahtevku 33, označena s tem, da je navedena povprečna velikost delcev od 150 do 350 mikrometrov.34. The population of claim 33, wherein said average particle size is from 150 to 350 micrometers.