SI21746A - Crystal forms of olanzapine and processes for their preparation - Google Patents

Abstract

The invention relates to a novel and well defined solvate form of olanzapine which is characterized by the x-ray structure in Figure 1 and by the NMR spectra in Figure 2 and which contains 2 molecules of water and one molecule of isopropanol per 2 molecules of olanzapine. The olanzapine used as a starting material for the preparation of the described olanzapine water-isopropanol mixed solvate can be in any form, e.g. it can be used when it is contained in reaction solution, crude, in filtrate when various solvents are present, or in anhydrous or any solvated form. In the prefered embodiment the herein prepared and described olanzapine water-isopropanol mixed solvate is used for the preparation of form I of olanzapine.

Description

Predloženi izum spada na področje organske kemije in se nanaša na novo mešano solvatno obliko 2-metil-4-(4-metil-1 -piperazinil)-1077-tieno[2,3-Z>][ 1,5]benzodiazepina (v nadaljnjem besedilu imenovano z njenim generičnim imenom olanzapin), na postopek za njeno pripravo in postopek za pripravo polimorfne oblike I olanzapina.The present invention relates to the field of organic chemistry and relates to a new mixed solvate form of 2-methyl-4- (4-methyl-1-piperazinyl) -1077-thieno [2,3-Z>] [1,5] benzodiazepine (in hereinafter referred to as its generic name olanzapine) to a process for its preparation and a process for the preparation of polymorphic form I of olanzapine.

Za olanzapin je prikazano, da ima visoko aktivnost za centralni živčni sistem in je uporaben tudi za zdravljenje shizofrenije in podobnih motenj, akutne manije, stanj blage tesnobe in psihoze.Olanzapine has been shown to have high activity for the central nervous system and is also useful for the treatment of schizophrenia and related disorders, acute mania, mild anxiety and psychosis.

TEHNIČNI PROBLEMTECHNICAL PROBLEM

V postopkih iz stanja tehnike se uporabljajo topila, kot sta metilenklorid in acetonitril, za kristalizacijo oblike I olanzapina, vendar pa le-ti pogosto ne vodijo do zadovoljivih celotnih dobitkov oblike I olanzapina. Poleg tega ti postopki iz stanja tehnike pogosto ne vodijo do olanzapina, ki ima čistočo, ki je zadovoljiva za pripravo farmacevtskih formulacij, ker so prisotne nečistote, ki jih je težko odstraniti po postopkih iz stanja tehnike.In the prior art, solvents such as methylene chloride and acetonitrile are used to crystallize form I olanzapine, but these often do not lead to satisfactory total yields of form I olanzapine. In addition, these prior art procedures often do not lead to olanzapine having a purity satisfactory for the preparation of pharmaceutical formulations because impurities that are difficult to remove by prior art are present.

Poleg tega še vedno obstaja potreba po izboljšanem postopku za pripravo očiščenega olanzapina, s katerim bi se izognili zgoraj navedenim pomanjkljivostim in bi dobili olanzapin s čistočo, zaradi katere bi bil zelo prikladen za pripravo farmacevtskih formulacij.In addition, there is still a need for an improved process for the preparation of purified olanzapine, to avoid the above disadvantages and to obtain olanzapine with a purity that would make it very suitable for the preparation of pharmaceutical formulations.

Nadalje obstaja potreba po prekurzorjih, ki bi dopuščali enostavno pripravo polimorfnih oblik olanzapina ali pretvorbo v druge oblike olanzapina.Furthermore, there is a need for precursors that would allow the easy preparation of olanzapine polymorphic forms or conversion to other forms of olanzapine.

Ti problemi so rešeni s predloženim izumom.These problems are solved by the present invention.

STANJE TEHNIKEBACKGROUND OF THE INVENTION

Britanski patent GB 1 533 235 opisuje antipsihotično učinkovite tienobenzodiazepine z generično formulo, ki pokriva tudi olanzapin.British Patent GB 1 533 235 describes antipsychotically effective thienobenzodiazepines with a generic formula also covering olanzapine.

US-patent 5,229,382 opisuje eksplicitno olanzapin. Opisan postopek za njegovo sintezo nadalje vključuje kristalizacijo iz acetonitrila, kristalizirana oblika ima tališče pri 195 °C.US Patent 5,229,382 explicitly describes olanzapine. The process described for its synthesis further includes crystallization from acetonitrile, the crystallized form having a melting point at 195 ° C.

V EP-B-733 635 zahtevajo zaščito za kristalinično obliko II olanzapina in za to polimorfno obliko je navedeno, daje bolj stabilna kot material, pridobljen v skladu z US 5,229,382, kije imenovan oblika I olanzapina. Tako oblika I kot tudi oblika II olanzapina sta določeni npr. z rentgenskimi podatki. Pripravo bolj stabilne oblike II olanzapina izvedejo z raztapljanjem olanzapina tehnične kvalitete v etilacetatu in kristalizacijo iz dobljene raztopine po kateremkoli kovencionalnem postopku, kot so cepljenje, hlajenje, strganje stekla reakcijske posode ali druge običajne tehnike.EP-B-733 635 requires protection for crystalline form II of olanzapine, and this polymorphic form is said to be more stable than material obtained in accordance with US 5,229,382, which is called form I of olanzapine. Both Form I and Form II of olanzapine are determined e.g. with X-ray data. The preparation of the more stable form II of olanzapine is carried out by dissolving olanzapine of technical quality in ethyl acetate and crystallizing from the resulting solution by any conventional method such as grafting, cooling, scraping the reaction vessels or other conventional techniques.

WO 02/18390 opisuje monohidratno obliko I in dihidratno obliko I olanzapina, postopek za njuno pripravo in postopek za pripravo oblike I olanzapina, ki obsega stopnje: mešanje monohidratne oblike I olanzapina ali surovega olanzapina ali oblike II olanzapina v metilenkloridu pri refluksu, hlajenje, filtriranje in sušenje. Prav tako je opisano, da ponavljanje postopka, opisanega v US 5,229,382, primer 1, podprimer 4 ne vodi do tvorbe oblike I olanzapina.WO 02/18390 describes monohydrate form I and dihydrate form I of olanzapine, a process for their preparation and a process for preparing form I of olanzapine, comprising the steps of: mixing olanzapine monohydrate or crude olanzapine or form II olanzapine in methylene chloride, refluxing, cooling and drying. It is also described that repeating the process described in US 5,229,382, example 1, sub-example 4 does not lead to the formation of form I olanzapine.

W0 03/101997 se nanaša na postopke za pripravo oblike I olanzapina z uravnavanjem pH-vrednosti raztopine.WO 03/101997 relates to processes for the preparation of form I olanzapine by adjusting the pH of the solution.

WO 03/055438 opisuje kristalizacijo iz etanola in nato pretvorbo etanolnega solvata v polimorfno obliko I olanzapina.WO 03/055438 describes crystallization from ethanol and then conversion of an ethanol solvate to polymorphic form I of olanzapine.

US-patent 5,637,584 opisuje (mono)metilenkloridno solvatno obliko olanzapina in postopek za njeno pretvorbo v polimorfno obliko I olanzapina.US Patent 5,637,584 describes the (mono) methylene chloride solvate form of olanzapine and the process for its conversion to polymorphic form I of olanzapine.

EP-B-733 634 se nanaša na tri specifične solvate olanzapina, in sicer na metanolne, etanolne in 1-propanolne solvate, in na postopek za pripravo oblike II olanzapina s sušenjem ustreznega solvata.EP-B-733 634 relates to three specific olanzapine solvates, namely methanolic, ethanol and 1-propanol solvates, and a process for the preparation of form II olanzapine by drying the corresponding solvate.

V WO 03/097650 sta opisani dve novi mešani solvatni obliki, mešani voda/metilenkloridni in voda/DMSO solvat, postopki za pripravo le-teh in njihove pretvorbe v polimorfno obliko I.WO 03/097650 describes two new mixed solvate forms, mixed water / methylene chloride and water / DMSO solvate, processes for preparing them and converting them to polymorph I.

WO 04/006933 A2 opisuje pripravo pripravka oblike I, nekatere psevdopolimorfne oblike, in sicer izopropanolni solvat, acetonitril/metilenklorid/vodni mešani solvat in acetonitril/vodni mešani solvat olanzapina, polimorfna oblika A, in postopke za njihovo pripravo.WO 04/006933 A2 describes the preparation of Form I preparation, certain pseudopolymorphic forms, namely isopropanol solvate, acetonitrile / methylene chloride / aqueous mixed solvate, and acetonitrile / aqueous mixed solvate of olanzapine, polymorphic Form A, and processes for their preparation.

KRATEK OPIS SLIKBRIEF DESCRIPTION OF THE DRAWINGS

Sl. 1 prikazuje ORTEP-pogled asimetrične enote Ci7H2oN₄S.H₂0.1/2(C3H70H). Poudariti je treba, daje na sl. 1 populacija neurejene izopropanolne molekule 0,50.FIG. 1 shows an ORTEP view of an asymmetric unit Ci7H2oN ₄ SH ₂ 0.1 / 2 (C3H70H). It should be emphasized that in FIG. 1 population of disordered isopropanol molecule 0.50.

Sl. 2 prikazuje NMR-spekter Ci7H₂oN₄S.H₂0.1/2(C3H₇OH).FIG. 2 shows the NMR spectrum of C ₇ H ₂ oN ₄ SH ₂ 0.1 / 2 (C ₃ H ₇ OH).

GLAVNA VSEBINA IZUMAMAIN CONTENT OF THE INVENTION

Predloženi izum se nanaša na novo in dobro definirano solvatno obliko olanzapina, ki je označena z rentgensko strukturo na sl. 1 in z NMR-spektrom na sl. 2, ki vsebuje 2 molekuli vode in 1 molekulo izopropanola na 2 molekuli olanzapina. Ta izopropanol/vodni mešani solvat olanzapina pripravimo iz topilne zmesi izopropanol/voda.The present invention relates to a new and well-defined solvate form of olanzapine, characterized by the X-ray structure of FIG. 1 and with the NMR spectrum of FIG. 2 containing 2 molecules of water and 1 molecule of isopropanol per 2 molecules of olanzapine. This isopropanol / aqueous mixed olanzapine solvate is prepared from an isopropanol / water solvent mixture.

Topilna zmes obsega izopropanol in vodo v razmerju 9-35 volumskih delov izopropanola na 1 volumski del vode. Prednostno je to razmerje 9:1, bolj prednostno 20:1 in najbolj prednostno 35:1.The solvent mixture comprises isopropanol and water in a ratio of 9-35 parts by volume of isopropanol per 1 volume of water. Preferably this ratio is 9: 1, more preferably 20: 1 and most preferably 35: 1.

Olanzapin, uporabljen kot izhodni material, je lahko v katerikoli obliki, npr. lahko je v reakcijski raztopini, v surovi obliki, v filtratu, brezvodni, solvatirani ali hidratirani obliki ali v obliki zmesi le-teh.Olanzapine used as starting material may be in any form, e.g. it may be in the reaction solution, in the raw form, in the filtrate, in the anhydrous, solvated or hydrated form or in the form of mixtures thereof.

Nepričakovano smo ugotovili, da lahko pripravo izopropanol/vodnega mešanega solvata olanzapina enostavno izvedemo, če olanzapin kristaliziramo z uporabo topilne zmesi, ki obsega izopropanol in vodo. Na ta način odstranimo trdovratne nečistote iz aktivne spojine in lahko olanzapin tudi ponovno pridobimo iz filtratov.It has been unexpectedly found that the preparation of the isopropanol / aqueous mixed solvate of olanzapine can be easily performed if olanzapine is crystallized using a solvent mixture comprising isopropanol and water. In this way, the persistent impurities are removed from the active compound and olanzapine can also be recovered from the filtrates.

Postopek za pripravo oblike I olanzapina navadno vključuje raztapljanje izopropanol/vodnega mešanega solvata olanzapina v topilni zmesi, ki obsega metilenklorid, in nato kristaliziranje in ponovno pridobivanje produkta s konvencionalnimi postopki. Z uporabo gornjih kristalizacij skih razmer je mogoče izolirati obliko I olanzapina iz izopropanol/vodne mešane solvatne oblike olanzapina z dobitki, čistočo in kvaliteto, ki so vsi izboljšani v primerjavi s stanjem tehnike.The process for preparing Form I olanzapine typically involves dissolving the isopropanol / aqueous mixed solvate of olanzapine in a solvent mixture comprising methylene chloride and then crystallizing and recovering the product by conventional methods. Using the above crystallization conditions, it is possible to isolate form I olanzapine from the isopropanol / aqueous mixed solvate form olanzapine with yields, purity and quality, all of which are improved in comparison with the prior art.

Obliko I olanzapina je precej težko pripraviti v znatno čisti obliki, ker je prednostna tvorba termodinamično bolj stabilne oblike II. Po postopku v smislu predloženega izuma lahko pripravimo v znatno čisto obliko I brez oblike II in solvatov.Form I olanzapine is quite difficult to prepare in a substantially pure form, because the formation of thermodynamically more stable Form II is preferred. According to the process of the present invention, it can be prepared in substantially pure Form I without Form II and solvates.

V nadaljevanju so opisane prednostne izvedbe postopka.The preferred embodiments of the process are described below.

PODROBEN OPIS IZUMADETAILED DESCRIPTION OF THE INVENTION

Predloženi izum se nanaša na novo in dobro definirano solvatno obliko olanzapina, ki je označena z rentgensko strukturo na sl. 1 in z NMR-spektrom na sl. 2 in ki vsebuje 2 molekuli vode in 1 molekulo izopropanola na 2 molekuli olanzapina.The present invention relates to a new and well-defined solvate form of olanzapine, characterized by the X-ray structure of FIG. 1 and with the NMR spectrum of FIG. 2 and containing 2 molecules of water and 1 molecule of isopropanol per 2 molecules of olanzapine.

Rentgenske difrakcijske podatke za posamezen kristal smo zbrali pri sobni temperaturi na difraktometru Nonius Kappa CCD s programsko opremo Nonius Collect. Strukturo smo razrešili z uporabo SIR97 (direktni postopki), čiščenje pa smo izvedli s programsko opremo X'tal.X-ray diffraction data for a single crystal were collected at room temperature on a Nonius Kappa CCD diffractometer using Nonius Collect software. The structure was resolved using SIR97 (direct procedures), and purification was performed using X'tal software.

Kristalografski podatki za izopropanol/vodni mešani solvat olanzapina, posebno interplaname razdalje (a, b, c) in koti (α, β, γ), so prikazani v tabeli 1.Crystallographic data for isopropanol / aqueous mixed solvate of olanzapine, especially the interplaname distances (a, b, c) and angles (α, β, γ), are shown in Table 1.

Tabela 1Table 1

prostorska skupina space group C2/c (št. 15) C2 / c (No 15) a a 2,455 nm 2,455 nm b b 1,251 nm 1,251 nm c c 1,531 nm 1,531 nm a a 90° 90 ° β β 125,3° 125.3 ° γ γ 90° 90 ° R R 0,059 0,059

NMR-podatki so pridobljeni na Varian UNITY+300 (300 MHz) spektrometru v CDCI3 s tetrametilsilanom kot internim standardom.NMR data were obtained on a Varian UNITY + 300 (300 MHz) spectrometer in CDCI3 with tetramethylsilane as an internal standard.

¹H NMR (CDCI3, 300 MHz) določitve signalov: ¹ H NMR (CDCI3, 300 MHz) signal determination:

kemijski premik δ_določitevchemical shift δ_determination

1,20 (3 H, d)1.20 (3H, d)

2,30 (3H, s)2.30 (3H, s)

2,34 (3H, s) 2,20-2,40 (2H, br s) 2,49 (4H, m)2.34 (3H, s) 2.20-2.40 (2H, br s) 2.49 (4H, m)

3,52 (4H, m)3.52 (4H, m)

4,03 (0,5 H, dq) 5,02 (H, širok s) 6,29 (H, širok s) 6,29-7,05 (4H, m)4.03 (0.5 H, dq) 5.02 (H, broad s) 6.29 (H, broad s) 6.29-7.05 (4H, m)

CH₃-izopropanolCH ₃ -isopropanol

4'-CH₃ 4'-CH ₃

2- CH3 H-voda 3'-CH₂ 2'-CH₂ 2- CH3 H-water 3'-CH ₂ 2'-CH ₂

CH-izopropanolCH-isopropanol

10-NH10-NH

3- CH 6,7, 8, 9-H3- CH 6,7, 8, 9-H

Olanzapin, uporabljen kot izhodni material za pripravo opisanega izopropanol/vodnega mešanega solvata olanzapina, je lahko v katerikoli obliki, npr. lahko ga uporabimo, če je vsebovan v reakcijski raztopini, v surovi obliki, v filtratu s prisotnimi različnimi topili, ali v brezvodni ali katerikoli solvatirani ali hidratirani obliki ali v zmesi le-teh.Olanzapine used as starting material for the preparation of the described isopropanol / aqueous mixed solvate of olanzapine may be in any form, e.g. it can be used if it is contained in the reaction solution, in the crude form, in the filtrate with various solvents present, or in anhydrous or any solvated or hydrated form or in a mixture thereof.

V prednostni izvedbi uporabimo izopropanol/vodni mešani solvat olanzapina, pripravljen in opisan v smislu predloženega izuma, za pripravo oblike I olanzapina visoke čistoče ali katerekoli druge solvatirane, hidratirane ali brezvodne oblike olanzapina.In a preferred embodiment, isopropanol / aqueous mixed solvate of olanzapine prepared and described in accordance with the present invention is used to prepare high-purity form I olanzapine or any other solvated, hydrated or anhydrous form of olanzapine.

Kadar tukaj opisani izopropanol/vodni mešani solvat olanzapina pripravimo iz reakcijske zmesi, zmes 4-amino-2-metil-10//-tieno[2,3-b][l,5]benzodiazepin hidroklorida in 1-metilpiperazina segrevamo v topilih z visokim vreliščem, kot npr. dimetilsulfoksidu in toluenu ali zmesi le-teh, prednostno ob refluksu, dokler ni reakcija dokončana, prednostno od 3 ure do 12 ur. Raztopino ohladimo, prednostno na temperature v območju od 90 °C do sobne temperature, in po izbiri del destilata oddestiliramo, prednostno pod vakuumom, pri temperaturah v območju od sobne do 90 °C, prednostno pri 50 °C do 90 °C.When the isopropanol / aqueous mixed solvate of olanzapine described here is prepared from the reaction mixture, the mixture of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride and 1-methylpiperazine is heated in solvents with high boiling point, such as dimethylsulfoxide and toluene or mixtures thereof, preferably at reflux, until the reaction is complete, preferably from 3 hours to 12 hours. The solution is cooled, preferably to temperatures in the range of 90 ° C to room temperature, and optionally distilled off, preferably under vacuum, at temperatures in the range of room temperature to 90 ° C, preferably at 50 ° C to 90 ° C.

V dobljeno raztopino, ki jo po izbiri delno oddestiliramo, prednostno pod vakuumom, pozneje in v poljubnem vrstnem redu dodamo izopropanol in vodo ali zmes le-teh. V prednostni izvedbi najprej dodamo izopropanol in nato vodo, da iniciiramo kristalizacijo.Isopropanol and water, or a mixture thereof, are subsequently added later in any order to the resulting solution, which is partially partially distilled off, preferably under vacuum. In a preferred embodiment, isopropanol is added first and then water is added to initiate crystallization.

Bistro raztopino ohladimo na temperature od temperature vrelišča do 10 °C in dodamo vodo, da iniciiramo kristalizacijo. Produkt nato odfiltriramo, speremo z izopropanolom, sušimo pri sobni temperaturi pod vakuumom do konstantne mase in dobimo izopropanol/vodni mešani solvat olanzapina.The clear solution was cooled to temperatures from boiling point to 10 ° C and water was added to initiate crystallization. The product was then filtered off, washed with isopropanol, dried at room temperature under vacuum to constant weight, to give isopropanol / aqueous mixed olanzapine solvate.

Kadar tukaj opisani izopropanol/vodni mešani solvat olanzapina pripravimo iz olanzapina v matičnih lužnicah, ki vsebujejo npr. metilenklorid, ali kadar ga pripravimo iz metilenkloridne solvatne oblike, topilo po izbiri oddestiliramo in v dobljeno raztopino, ki jo po izbiri delno oddestiliramo, prednostno pod vakuumom, pozneje in v poljubnem vrstnem redu dodamo izopropanol in vodo ali zmes le-teh. V prednostni izvedbi najprej dodamo izopropanol in nato vodo, da iniciiramo kristalizacijo kot zgoraj. Ko je kristalizacija dokončana oborino odfiltriramo in posušimo.When the isopropanol / aqueous mixed olanzapine solvate described herein is prepared from olanzapine in mother liquors containing e.g. methylene chloride, or when prepared from methylene chloride solvate form, the solvent is optionally distilled off, and isopropanol and water, or a mixture thereof, subsequently optionally distilled into the resulting solution, which is partially distilled off, preferably under vacuum, subsequently and in any order. In a preferred embodiment, isopropanol and then water are added first to initiate crystallization as above. When the crystallization is complete, the precipitate is filtered off and dried.

Olanzapin, uporabljen kot izhodni material za pripravo opisanega izopropanol/vodnega mešanega solvata olanzapina, je lahko tudi surovi olanzapin ali olanzapin v brezvodni ali katerikoli solvatirani ali hidratirani obliki ali v obliki zmesi le-teh. Olanzapin raztopimo s segrevanjem v izopropanolu in vodi, ki ju dodamo pozneje in v poljubnem vrstnem redu, ali v zmesi le-teh. V primeru, da olanzapin raztopimo v vodi, dodamo izopropanol pozneje, in v primeru, da olanzapin raztopimo najprej v izopropanolu, dodamo vodo pozneje. Obe topili lahko dodamo tudi dodatno pozneje in v poljubnem vrstnem redu.Olanzapine, used as a starting material for the preparation of the described isopropanol / aqueous mixed solvate of olanzapine, may also be crude olanzapine or olanzapine in anhydrous or any solvated or hydrated form or in the form of mixtures thereof. Olanzapine is dissolved by heating in isopropanol and water, which are added subsequently and in any order, or in a mixture thereof. If olanzapine is dissolved in water, isopropanol is added later, and if olanzapine is dissolved in isopropanol first, water is added later. Both solvents can also be added at a later time and in any order.

Bistro raztopino ohladimo na temperature od temperature vrelišča do 10 °C in dodamo vodo, da iniciiramo kristalizacijo. Produkt nato odfiltriramo, speremo z izopropanolom, sušimo pri sobni temperaturi pod vakuumom do konstantne mase in tako dobimo izopropanol/vodni mešani solvat olanzapina.The clear solution was cooled to temperatures from boiling point to 10 ° C and water was added to initiate crystallization. The product was then filtered off, washed with isopropanol, dried at room temperature under vacuum to constant weight to give isopropanol / aqueous mixed olanzapine solvate.

Opisani izopropanol/vodni mešani solvat olanzapina, pripravljen po kateremkoli navedenem postopku, ima visoko kvaliteto in je v bistvu brez nečistot in ga tako lahko uporabimo za pripravo različnih drugih solvatov, hidratov ali zmesi le-teh.The described isopropanol / aqueous mixed olanzapine solvate, prepared by any of the foregoing methods, is of high quality and substantially free of impurities and can thus be used to prepare various other solvates, hydrates or mixtures thereof.

Po dokončani kristalizaciji oborino odfiltriramo in posušimo. Dobljeni izopropanol/vodni mešani solvat olanzapina lahko po izbiri prekristaliziramo.After crystallization is complete, the precipitate is filtered off and dried. The isopropanol / aqueous mixed olanzapine solvate obtained can be optionally recrystallized.

Med postopkom kristalizacije ali obarjanja v katerikoli izvedbi v smislu izuma po izbiri dodamo dinatrijevo sol etilendiaminotetraocetne kisline in po mešanju neraztopljeni material vroče odfiltriramo.During the process of crystallization or precipitation in any embodiment of the invention, the disodium salt of ethylenediaminotetraacetic acid is optionally added and, after stirring, the dissolved material is filtered hot.

Za pripravo oblike I izopropanol/vodni mešani solvat olanzapina, ki ga pripravimo po kateremkoli zgoraj navedenem načinu, nato suspendiramo v metilenkloridu in segrevamo, dokler ne dobimo bistre raztopine. Potem ko dobimo bistro raztopino, del topila uparimo pod vakuumom ali po izbiri pri atmosferskem tlaku ali kombinaciji leteh pri temperaturah v območju od vrelišča raztopine do -20 °C, da izoliramo metilenkloridni solvat olanzapina.To prepare Form I, the isopropanol / aqueous mixed solvate of olanzapine, prepared by any of the above methods, is then suspended in methylene chloride and heated until a clear solution is obtained. After obtaining a clear solution, the solvent portion is evaporated in vacuo or optionally at atmospheric pressure or in combination with the fly at temperatures ranging from the boiling point of the solution to -20 ° C to isolate the olanzapine methylene chloride solvate.

V drugi prednostni izvedbi izopropanol/vodni mešani solvat olanzapina suspendiramo v metilenkloridu in segrevamo do 35 °C do bistre raztopine in dodamo sušilno sredstvo, prednostno drierit (brezvodni CaSOj.In another preferred embodiment, the isopropanol / aqueous mixed solvate of olanzapine is suspended in methylene chloride and heated to 35 ° C to a clear solution, and a drying agent, preferably drierite (anhydrous CaSO3, is added).

Fakultativno uporabimo cepljenje z večjimi količinami kristaliničnega metilenkloridnega solvata.Vaccination with higher amounts of crystalline methylene chloride solvate is optional.

K metilenkloridnem solvatu olanzapina dodamo izopropanol v mas./vol. razmerju od 2 do 5, prednostno od 2 do 3, in suspenzijo mešamo pri temperaturi od 15 °C do 35 °C, zlasti pri sobni temperaturi od 15 min do 90 min, prednostno od 30 min do 60 min. Fakultativno uporabimo cepljenje s polimorfno obliko I. Metilenkloridni solvat po izbiri suspendiramo v izopropanolu, prenasičenem z olanzapinom, z mas./vol. razmerjem od 2 do 30, prednostno od 3 do 15, in suspenzijo mešamo pri temperaturi od 5 °C do 50 °C, zlasti pri sobni temperaturi od 15 min do 90 min, prednostno od 30 min do 60 min. Proizvod odfiltriramo in sušimo pod vakuumom pri sobni temperaturi do konstantne mase, nato pri 50 °C do konstantne mase. Izoliramo obliko I olanzapina.To the olanzapine methylene chloride solvate, isopropanol in w / v was added. a ratio of 2 to 5, preferably 2 to 3, and the suspension is stirred at a temperature of 15 ° C to 35 ° C, especially at room temperature from 15 minutes to 90 minutes, preferably from 30 minutes to 60 minutes. Optional polymorphic form I vaccination is used. The methylene chloride solvate is optionally suspended in olanzapine-supersaturated isopropanol with w / v. with a ratio of from 2 to 30, preferably from 3 to 15, and the suspension is stirred at a temperature of 5 ° C to 50 ° C, especially at room temperature from 15 min to 90 min, preferably from 30 min to 60 min. The product was filtered off and dried under vacuum at room temperature to constant weight, then at 50 ° C to constant weight. Form I olanzapine is isolated.

Postopke, znane iz stanja tehnike, tudi lahko uporabimo za pripravo oblike I izopropanol/vodnega mešanega solvata olanzapina, opisanega tukaj.Methods known in the art can also be used to prepare the Form I isopropanol / aqueous mixed solvate of olanzapine described herein.

Predloženi izum je ponazorjen z naslednjimi Primeri, ne da bi bil omejen z njimi.The present invention is illustrated by the following Examples without being limited thereto.

Priprava izopropanol/vodnega mešanega solvata olanzapinaPreparation of isopropanol / aqueous mixed solvate of olanzapine

Primer 1Example 1

Zmes 4-amino-2-metil-10//-tieno[2,3-b][l,5]benzodiazepin hidroklorida (26,6 g), 1metilpiperazina (92 ml), dimetilsulfoksida (120 ml) in toluena (120 ml) segrevamo ob refluksu 4 ure. Raztopino ohladimo na 95 °C in oddestiliramo 200 ml destilata pod vakuumom. Ostanek ohladimo na sobno temperaturo, dodamo izopropanol (180 ml), raztopino nadalje ohladimo na 0 °C in dodamo vodo (36 ml), da iniciiramo kristalizacijo. Po dokončani kristalizaciji oborino odfiltriramo in speremo z izopropanolom (20 ml). Vlažen produkt suspendiramo v izopropanolu (200 ml) in segrevamo do refluksa, da dobimo bistro raztopino. Dodamo dinatrijevo sol etilen diaminotetraocetne kisline (3 g) in suspenzijo mešamo 1 uro. Neraztopljen material vroče filtriramo. Bistro raztopino ohladimo na 25 °C in dodamo vodo (6 ml), da iniciiramo kristalizacijo. Suspenzijo ohladimo na 0 °C, po dokončani kristalizaciji pa jo odfiltriramo in speremo z izopropanolom (10 ml). Produkt sušimo pri sobni temperaturi pod vakuumom do konstantne mase. Dobitek: 22,84 g. Izguba pri sušenju (140 °C): 13,6 %. Vsebnost vode (KF): 5,12 %.A mixture of 4-amino-2-methyl-10 N -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (26.6 g), 1methylpiperazine (92 ml), dimethyl sulfoxide (120 ml) and toluene (120 ml) is heated at reflux for 4 hours. The solution was cooled to 95 ° C and distilled 200 ml of the distillate under vacuum. The residue was cooled to room temperature, isopropanol (180 ml) was added, the solution was further cooled to 0 ° C and water (36 ml) was added to initiate crystallization. After crystallization was complete, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to give a clear solution. The disodium salt of ethylene diaminotetraacetic acid (3 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 25 ° C and water (6 ml) was added to initiate crystallization. The suspension was cooled to 0 ° C, and after crystallization was complete, it was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 22.84 g. Loss on drying (140 ° C): 13.6%. Water content (KF): 5.12%.

Primer 2Example 2

Zmes 4-amino-2-metil-10//-tieno[2,3-b][l,5]benzodiazepin hidroklorida (26,6 g), 1metilpiperazina (92 ml), dimetilsulfoksida (36 ml) in toluena (120 ml) segrevamo ob refluksu 4 ure. Raztopino ohladimo na 95 °C in oddestiliramo 80 ml destilata pod vakuumom. Ostanek ohladimo na sobno temperaturo, dodamo izopropanol (180 ml), raztopino nadalje ohladimo na 0 °C in dodamo vodo (36 ml), da iniciiramo kristalizacijo. Po dokončani kristalizaciji oborino odfiltriramo in speremo z izopropanolom (20 ml). Vlažen produkt suspendiramo v izopropanolu (200 ml) in segrevamo do refluksa, da dobimo bistro raztopino. Dodamo dinatrijevo sol etilen diaminotetraocetne kisline (3 g) in suspenzijo mešamo 1 uro. Neraztopljen material vroče filtriramo. Bistro raztopino ohladimo na 35 °C in dodamo vodo (6 ml), da iniciiramo kristalizacijo. Suspenzijo ohladimo na 0 °C, po dokončani kristalizaciji pa jo odfiltriramo in speremo z izopropanolom (10 ml). Produkt sušimo pri sobni temperaturi pod vakuumom do konstantne mase. Dobitek: 21,98 g. Izguba pri sušenju (140 °C): 13,2 %. Vsebnost vode (KF): 5,09 %. Preizkus za izopropanol (GC): 8,55 %.A mixture of 4-amino-2-methyl-10 N -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (26.6 g), 1methylpiperazine (92 ml), dimethyl sulfoxide (36 ml) and toluene (120 ml) is heated at reflux for 4 hours. The solution was cooled to 95 ° C and distilled 80 ml of distillate under vacuum. The residue was cooled to room temperature, isopropanol (180 ml) was added, the solution was further cooled to 0 ° C and water (36 ml) was added to initiate crystallization. After crystallization was complete, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to give a clear solution. The disodium salt of ethylene diaminotetraacetic acid (3 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 35 ° C and water (6 ml) was added to initiate crystallization. The suspension was cooled to 0 ° C, and after crystallization was complete, it was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 21.98 g. Loss on drying (140 ° C): 13.2%. Water content (KF): 5.09%. Isopropanol (GC) test: 8.55%.

Primer 3Example 3

Zmes 4-amino-2-metil-10//-tieno[2,3-b][l,5]benzodiazepin hidroklorida (26,6 g), 1metilpiperazina (92 ml), dimetilsulfoksida (36 ml) in toluena (120 ml) segrevamo ob refluksu 4 ure. Raztopino ohladimo na 95 °C in oddestiliramo 120 ml destilata pod vakuumom. Ostanek ohladimo na sobno temperaturo, dodamo izopropanol (180 ml), raztopino nadalje ohladimo na 0 °C in dodamo vodo (36 ml), da iniciiramo kristalizacijo. Po dokončani kristalizaciji oborino odfiltriramo in speremo z izopropanolom (20 ml). Vlažen produkt suspendiramo v izopropanolu (200 ml) in segrevamo do refluksa, da dobimo bistro raztopino. Dodamo dinatrijevo sol etilen diaminotetraocetne kisline (3 g) in suspenzijo mešamo 1 uro. Neraztopljen material vroče filtriramo. Bistro raztopino ohladimo na 35 °C in dodamo vodo (6 ml), da iniciiramo kristalizacija. Suspenzijo ohladimo na 0 °C, po dokončani kristalizaciji pa jo odfiltriramo in speremo z izopropanolom (10 ml). Produkt sušimo pri sobni temperaturi pod vakuumom do konstantne mase. Dobitek: 24,35 g. Izguba pri sušenju (140 °C): 13,5 %. Vsebnost vode (KF): 5,05 %.A mixture of 4-amino-2-methyl-10 N -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (26.6 g), 1methylpiperazine (92 ml), dimethyl sulfoxide (36 ml) and toluene (120 ml) is heated at reflux for 4 hours. The solution was cooled to 95 ° C and distilled 120 ml of the distillate under vacuum. The residue was cooled to room temperature, isopropanol (180 ml) was added, the solution was further cooled to 0 ° C and water (36 ml) was added to initiate crystallization. After crystallization was complete, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to give a clear solution. The disodium salt of ethylene diaminotetraacetic acid (3 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 35 ° C and water (6 ml) was added to initiate crystallization. The suspension was cooled to 0 ° C, and after crystallization was complete, it was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 24.35 g. Loss on drying (140 ° C): 13.5%. Water content (KF): 5.05%.

Primer 4Example 4

Brezvodni olanzapin (10 g) suspendiramo v izopropanolu (108 ml) in segrevamo do refluksa, da dobimo bistro raztopino. Raztopino počasi ohladimo. Pri 57 °C dodamo vodo (6 ml), da iniciiramo kristalizacijo. Suspenzijo ohladimo na 0 °C, po dokončani kristalizaciji pa jo odfiltriramo in speremo z izopropanolom (5 ml). Produkt sušimo pri sobni temperaturi pod vakuumom do konstantne mase. Dobitek: 10,97 g. Izguba pri sušenju (140 °C): 13,3 %. Vsebnost vode (KF): 5,13 %.Anhydrous olanzapine (10 g) was suspended in isopropanol (108 ml) and heated to reflux to give a clear solution. Cool the solution slowly. Water (6 ml) was added at 57 ° C to initiate crystallization. The suspension was cooled to 0 ° C and, after crystallization, was filtered off and washed with isopropanol (5 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 10.97 g. Loss on drying (140 ° C): 13.3%. Water content (KF): 5.13%.

Primer 5Example 5

Olanzapin, dobljen iz matičnih lužnic (60 g), suspendiramo v izopropanolu (650 ml) in segrevamo do refluksa, da dobimo bistro raztopino. Dodamo dinatrijevo sol etilendiaminotetraocetne kisline (7,9 g) in suspenzijo mešamo 1 uro. Neraztopljen material vroče filtriramo. Bistro raztopino ohladimo na 25 °C in dodamo vodo (16 ml), da iniciiramo kristalizacijo.Olanzapine obtained from mother liquors (60 g) was suspended in isopropanol (650 ml) and heated to reflux to give a clear solution. Ethylenediaminotetraacetic acid disodium salt (7.9 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 25 ° C and water (16 ml) was added to initiate crystallization.

Suspenzijo ohladimo na 0 °C, po dokončani kristalizaciji jo odfiltriramo in speremo z izopropanolom (50 ml). Produkt sušimo pri sobni temperaturi pod vakuumom do konstantne mase. Dobitek: 57,64 g. Izguba pri sušenju (140 °C): 13,5 %. Vsebnost vode (KF): 5,26 %.The suspension was cooled to 0 ° C, after crystallization was complete, filtered off and washed with isopropanol (50 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 57.64 g. Loss on drying (140 ° C): 13.5%. Water content (KF): 5.26%.

Priprava metilenkloridnega solvata olanzapinaPreparation of the methylene chloride solvate of olanzapine

Primer 6Example 6

Izopropanol/vodni mešani solvat olanzapina (lig) suspendiramo v metilenkloridu (132 ml) in segrevamo, da dobimo bistro raztopino. Oddestiliramo 66 ml topila. Dodamo nadaljnjih 16 ml metilenklorida in ga oddestiliramo. Zmes vroče filtriramo in koncentriramo pod vakuumom do volumna 36 ml. Med vakuumsko destilacijo raztopino ohladimo in Produkt oborimo. Produkt odfiltriramo in sušimo pod vakuumom pri sobni temperaturi do konstantne mase. Dobitek: 8,47 g. Izguba pri sušenju (140 °C): 12,7 %. Vsebnost vode (KF): 0,40 %.The isopropanol / aqueous mixed solvate of olanzapine (lig) was suspended in methylene chloride (132 ml) and heated to give a clear solution. Distill off with 66 ml of solvent. A further 16 ml of methylene chloride was added and distilled off. The mixture was filtered hot and concentrated under vacuum to a volume of 36 ml. During vacuum distillation, the solution is cooled and the product precipitated. The product was filtered off and dried under vacuum at room temperature to constant weight. Yield: 8.47 g. Loss on drying (140 ° C): 12.7%. Water content (KF): 0.40%.

Primer 7Example 7

Izopropanol/vodni mešani solvat olanzapina (30 g) suspendiramo v metilenkloridu (330 ml) in segrevamo do 35 °C, da dobimo bistro raztopino. Dodamo drierit (brezvodni CaSO₄, 45 g) in mešamo 1 uro. Suspenzijo vroče filtriramo in koncentriramo pod vakuumom do volumna 100 ml. Med vakuumsko destilacijo raztopino ohladimo in produkt oborimo. Produkt odfiltriramo in sušimo pod vakuumom pri sobni temperaturi do konstantne mase. Dobitek: 21,31 g. Izguba pri sušenju (140 °C): 11,3 %. Vsebnost vode (KF): 0,51 %.The isopropanol / aqueous mixed solvate of olanzapine (30 g) was suspended in methylene chloride (330 ml) and heated to 35 ° C to give a clear solution. Add drierite (anhydrous CaSO ₄ , 45 g) and stir for 1 hour. The suspension was hot filtered and concentrated under vacuum to a volume of 100 ml. During vacuum distillation, the solution is cooled and the product precipitated. The product was filtered off and dried under vacuum at room temperature to constant weight. Yield: 21.31 g. Loss on drying (140 ° C): 11.3%. Water content (KF): 0.51%.

Priprava oblike I olanzapinaPreparation of form I olanzapine

Primer 8Example 8

Metilenkloridni solvat olanzapina (10 g) suspendiramo v izopropanolu (20 ml). Suspenzijo mešamo pri sobni temperaturi 1 uro. Produkt odfiltriramo in sušimo pod vakuumom pri sobni temperaturi do konstantne mase, nato pa pri 50 °C do konstantne mase. Dobitek: 7,8 g.The olanzapine methylene chloride solvate (10 g) was suspended in isopropanol (20 ml). The suspension was stirred at room temperature for 1 hour. The product was filtered off and dried under vacuum at room temperature to constant mass and then at 50 ° C to constant mass. Yield: 7.8 g.

Primer 9Example 9

Metilenkloridni solvat olanzapina (10 g) suspendiramo v izopropanolu (150 ml, prednasičena raztopina z olanzapinom). Suspenzijo mešamo pri sobni temperaturi 1 uro. Proizvod odfiltriramo in sušimo pod vakuumom pri sobni temperaturi do konstantne mase, nato pa pri 50 °C do konstantne mase. Dobitek: 14,3 g.The olanzapine methylene chloride solvate (10 g) was suspended in isopropanol (150 ml, pre-saturated solution with olanzapine). The suspension was stirred at room temperature for 1 hour. The product was filtered off and dried under vacuum at room temperature to constant mass and then at 50 ° C to constant mass. Yield: 14.3 g.

Claims (8)

Patentni zahtevkiPatent claims 1. Izopropanol/vodni mešani solvat olanzapina, ki vsebuje 2 molekuli vode in 1 molekulo izopropanola na 2 molekuli olanzapina.An isopropanol / aqueous mixed solvate of olanzapine containing 2 molecules of water and 1 molecule of isopropanol per 2 molecules of olanzapine. 2. Izopropanol/vodni mešani solvat olanzapina, določen z rentgensko strukturo na sl.2. The isopropanol / aqueous mixed olanzapine solvate determined by the X-ray structure of FIG. 1.1. 3. Izopropanol/vodni mešani solvat olanzapina, določen z NMR-spektrom na sl. 2.3. The isopropanol / aqueous mixed solvate of olanzapine, determined by the NMR spectrum of FIG. 2. 4. Izopropanol/vodni mešani solvat olanzapina, ki je določen z NMR-spektrom v CDCI3 in vsebuje signale pri približno 1,20 ppm, 2,20-2,40 ppm in 4,03 ppm.4. Isopropanol / aqueous mixed solvate of olanzapine, determined by the NMR spectrum in CDCI3 and containing signals at about 1.20 ppm, 2.20-2.40 ppm and 4.03 ppm. 5. Postopek za pripravo izopropanol/vodnega mešanega solvata olanzapina po zahtevku 1, označen s tem, da topilna zmes vsebuje izopropanol in vodo v razmerju 9 do 35 volumskih delov izopropanola na 1 volumski del vode, prednostno je razmerje 9:1, bolj prednostno 20:1 in najbolj prednostno 35:1.5. A process for the preparation of an isopropanol / aqueous mixed solvate of olanzapine according to claim 1, characterized in that the solvent mixture contains isopropanol and water in a ratio of 9 to 35 parts by volume of isopropanol per 1 volume of water, preferably a ratio of 9: 1, more preferably 20 : 1 and most preferably 35: 1. 6. Uporaba izopropanol/vodnega mešanega solvata olanzapina po zahtevku 1 za pripravo oblike I olanzapina.Use of the isopropanol / aqueous mixed solvate of olanzapine according to claim 1 for the preparation of form I olanzapine. 7. Uporaba izopropanol/vodnega mešanega solvata olanzapina po zahtevku 1 za pripravo kateregakoli drugega solvata, hidratiranih oblik olanzapina ali zmesi le-teh.Use of the isopropanol / aqueous mixed solvate of olanzapine according to claim 1 for the preparation of any other solvate, hydrated forms of olanzapine or mixtures thereof. 8. Uporaba izopropanol/vodnega mešanega solvata olanzapina po zahtevku 1 za pripravo brezvodnih oblik olanzapina.Use of the isopropanol / aqueous mixed solvate of olanzapine according to claim 1 for the preparation of anhydrous forms of olanzapine.