DE2449927C2 - New stable polymorphic crystalline form of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one and a pharmaceutical preparation containing this polymorphic form - Google Patents
New stable polymorphic crystalline form of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one and a pharmaceutical preparation containing this polymorphic formInfo
- Publication number
- DE2449927C2 DE2449927C2 DE2449927A DE2449927A DE2449927C2 DE 2449927 C2 DE2449927 C2 DE 2449927C2 DE 2449927 A DE2449927 A DE 2449927A DE 2449927 A DE2449927 A DE 2449927A DE 2449927 C2 DE2449927 C2 DE 2449927C2
- Authority
- DE
- Germany
- Prior art keywords
- polymorphic
- dibenzo
- hexahydro
- pyran
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Saccharide Compounds (AREA)
Description
2. Pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt einer neuen stabilen polymorphen f2. Pharmaceutical preparation, characterized by a content of a new stable polymorphic f
Form von 1 -Hydroxy-3-( 1 ',1 '-dimethylheptyl)-o,6-dimethyl-6,6a,7,8,l0,10a-hexahydro-9H-dibenzo[b,d]pyran- gForm of 1-hydroxy-3- (1 ', 1' -dimethylheptyl) -o, 6-dimethyl-6,6a, 7,8, 10,10a-hexahydro-9H-dibenzo [b, d] pyran- g
9-on gemäß Anspruch 1 als Wir kstoff und üblichen pharmazeutischen Hilfs- und Trägermitteln. ® 9-one according to Claim 1 as a substance and customary pharmaceutical auxiliaries and carriers. ®
30· Die Erfindung betrifft eine neue stabile polymorphe kristalline Form von l-Hydroxy-3-(r,r-dimethylhep- ξ 30 · The invention relates to a new stable polymorphic crystalline form of l-hydroxy-3- (r, r-dimethylhep- ξ
tyl)-6,6-dimethyI-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-on, die lange Zeit nach oraler Verabrei- |tyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, which is long after oral administration |
chung des Arzneimittels zur Ausbildung beachtlicher Blutspiegel bei Säugetieren befähigt ist.The preparation of the drug is capable of producing considerable blood levels in mammals.
l-Hydroxy-3-alkyI-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one, deren Äther und Ester sind in US-PS 35 07 885 als Zwischenprodukte zur Herstellung von As- oder zf-Tetrahydrocannabinolen (Aa- oder A^-THC) beschrieben. Außer der Verwendung als Zwischenprodukte ist für diese Verbindungen keine andere Anwendungsart angegeben.l-Hydroxy-3-alkyI-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones, the ethers and esters of which are in US PS 35 07 885 described as intermediates for the production of A s - or zf-tetrahydrocannabinols (A a - or A ^ -THC) . Apart from their use as intermediates, no other type of application is specified for these compounds.
A^-THC und andere strukturell verwandte Dibenzopyrane, die man entweder aus natürlichen Quellen oder nach verschiedenen Syntheseverfahren erhalten kann, sind als in wäßrigen Medien äußerst unlöslich bekannt. Es bestand daher immer das Problem der Bestimmung der pharmakologischen Wirkungen dieser Verbindungsart | A ^ -THC and other structurally related dibenzopyrans, which can be obtained either from natural sources or by various synthetic methods, are known to be extremely insoluble in aqueous media. There has therefore always been the problem of determining the pharmacological effects of this type of compound |
nach oraler Verabreichung, da man überhaupt nicht wissen konnte, welche Menge dieser äußerst unlöslichen |after oral administration, since it was impossible to know what amount of this extremely insoluble |
Substanzen nach oraler Verabreichung tatsächlich resorbiert wurde. Diese Schwierigkeit der Ermittlung des Ausmaßes der Resorption dieser Verbindungen wird noch weiter kompliziert durch die Tatsache, daß die Verbindungen in festem Zustand in mehreren polymorphen Formen vorliegen können.Substances after oral administration was actually absorbed. This difficulty in identifying the The extent to which these compounds are absorbed is further complicated by the fact that the Solid state compounds can exist in several polymorphic forms.
Erfindungsgemäß wird nun eine neue stabile polymorphe Form von l-Hydroxy-3-(r,r-dimethylheptyl)-6,6-dimethy!-6,6a,7,8,l0,10a-hexahydro-9H-dibenzo[b.d]pyran-9-on geschaffen, die über folgende physikalische Eigenschaften verfügt: Sie zeigt unter einem Polarisationsmikroskop Doppelbrechung, weist bei der Differeniialthermoanalyse bei 1560C und 1620C Endothermen auf und verfügt im pulverförmigen Zustand über folgendes Röntgenbeugungsspektrum, wenn man bei einer mit einem Vanadiumfilter gefilterten Chromstrahlung mit einer Wellenlänge von 0,22896 nm arbeitet:According to the invention, a new stable polymorphic form of l-hydroxy-3- (r, r-dimethylheptyl) -6,6-dimethy! -6,6a, 7,8, 10,10a-hexahydro-9H-dibenzo [bd] created pyran-9-one, which has the following physical properties: It shows birefringence under a polarization microscope, shows endotherms in differential thermal analysis at 156 ° C. and 162 ° C. and has the following X-ray diffraction spectrum in the powdery state, if you look at one with a Vanadium filter filtered chromium radiation with a wavelength of 0.22896 nm works:
50 55 60 50 55 60
Die erfindungsgemäße neue polymorphe kristalline Form wird wie folgt hergestellt: Eine äthanolische Lösung einer physiologisch nicht verfügbaren, oral nicht absorbierbaren polymorphen kristallinen Form von 1 -Hydroxy-3-(rir-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a'hexahydro-9H-dibenzo[b,d]pyran-9-on, mit der sich nach oraler Verabreichung des Heilmittels an Säugetiere keine signifikanten Blutspiegel bilden lassen, und die durchThe novel polymorphic crystalline form according to the invention is produced as follows: An ethanolic solution of a physiologically unavailable, orally non-absorbable polymorphic crystalline form of 1-hydroxy-3- (r i r-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a'hexahydro-9H-dibenzo [b, d] pyran-9-one, with which no significant blood levels can be formed after oral administration of the medicinal product to mammals, and which by
Umkristallisieren aus Aceton oder Hexan hergestellt wurde, wird sehr schnell unter Rühren zu einer großen Menge Wasser gegeben. Das Dibenzopyranon, das in Wasser praktisch unlöslich ist, fällt sofort aus. Man rührt eine kurze Zeit weiter, worauf man den ausgefallenen Wirkstoff der gewünschten polymorphen Form mit den oben angegebenen physikalischen Eigenschaften abfiltriert und trocknet.Recrystallization from acetone or hexane will turn into a large one very quickly with stirring Amount of water given. The dibenzopyranone, which is practically insoluble in water, precipitates out immediately. One stirs a short time further, whereupon the precipitated active ingredient of the desired polymorphic form with the Filtered off physical properties given above and dried.
Um eine Umwandlung der neuen polymorphen Form in die üblicheren kristallinen Formen, wie man sie durch Umkristallisieren des Wirkstoffes aus Aceton oder Hexan erhält, zu vermeiden, müssen kristallisationshemmende Mittel zugesetzt werden, wie Polyvinylpyrrolidon, Methylcellulose, Natriumalginat, Dextran, Gelatine oder Akazie. Falls man mit solchen Mitteln arbeitet, dann sollte man diese dem Wasser zusetzen, bevor man diese' mit der äthanolischen Lösung des Wirkstoffes versetzt.To achieve a conversion of the new polymorphic form into the more common crystalline forms, how to get them through To avoid recrystallization of the active ingredient obtained from acetone or hexane, need crystallization-inhibiting Agents are added, such as polyvinylpyrrolidone, methyl cellulose, sodium alginate, dextran, gelatin or Acacia. If you work with such agents, then you should add them to the water before you use them the ethanolic solution of the active ingredient added.
Die neue polymorphe kristalline Form von l-Hydroxy-S-ilM'-dimethylheptyO-ö.o-dimethyl-ö.öaJ.S.lO.lOa-hexahydro-9H-dibenzo[b,d]pyran-9-on kann wahlweise auch hergestellt werden, indem man eine äthanolische Lösung der Verbindung herstellt und dann das Lösungsmittel durch Verdampfen bei einer Temperatur im Bereich von 20 bis 300C abzieht Hierzu verwendet man vorzugsweise einen Rotationsverdampfer. Die Verdampfungstemperatur läßt sich mühelos durch Einsatz eines großvolumigeri Wasserbades auf dem gewünschten Wt-rt halten.The new polymorphic crystalline form of l-hydroxy-S-ilM'-dimethylheptyO-ö.o-dimethyl-ö.öaJ.S.lO.lOa-hexahydro-9H-dibenzo [b, d] pyran-9-one can optionally can also be prepared by preparing an ethanolic solution of the compound and then removing the solvent by evaporation at a temperature in the range from 20 to 30 ° C. For this purpose, a rotary evaporator is preferably used. The evaporation temperature can easily be kept at the desired value by using a large-volume water bath.
Zur Herstellung einer pharmazeutischen Zubereitung vermischt man einen Teil l-Hydroxy-3-(I',r-dimethylheptyI)-6,6-dimethyI-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b.d]p >ran-9-on in einer, wie oben angegeben, hergestellten verhältnismäßig resorbierbaren polymorphen Form gründlich mit neuen Teilen Maisstärke, worauf man das erhaltene Gemisch in Teleskopgelatinekapseln gibt und an zwei Hunden bezüglich seiner Resorbierbarkeit untersucht Di«? Verbindung wird in Kapselform oral verabreicht. Es lassen sich die auch bei anderen oral resorbierbaren Formen oder bei parenteraler Injektion beobachteten Nebeneffekte auch hier feststellen, wie Kopfnicken, Schwanken des Körpers und Ataxie. Die Stärkepräparation in Kapselform wird zwei Wochen später erneut, und dann wiederum nach 10 Wochen untersucht, wobei man identische Ergebnisse erhält, was zeigt, daß die eriindungsgemäße polymorphe Form in Gegenwart von Stärke stabil ist. Andere polymorphe Formen von l-Hydroxy-3-(r,l'-dimethylheptyl)-6,6-dimethyI-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-on sind zwar in Lösung oder kjrz nach dem Vermischen mit Stärke wirksam, sie kristallisieren sich jedoch langsam um oder bilden einen Komplex mit Stärke, wodurch ihre Bioverfügbarkeit nachteilig beeinflußt wird.To produce a pharmaceutical preparation, a portion of l-hydroxy-3- (I ', r-dimethylheptyI) -6,6-dimethyI-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [bd] p > ran-9-on in a, as indicated above, produced relatively absorbable polymorphic form thoroughly with new parts of corn starch, whereupon one the mixture obtained in telescopic gelatine capsules and two dogs with regard to its absorbability examines Di «? Compound is administered orally in capsule form. It can also be taken orally with others absorbable forms or side effects observed with parenteral injection also determine here how Nodding of the head, swaying of the body and ataxia. The starch preparation in capsule form is two weeks examined again later, and then again after 10 weeks, with identical results, what shows that the polymorphic form according to the invention is stable in the presence of starch. Other polymorphic Forms of l-hydroxy-3- (r, l'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one While effective in solution or shortly after mixing with starch, they crystallize slowly transform or complex with starch, adversely affecting their bioavailability.
Die Erfindung wird anhand der folgenden Beispiele näher erläutertThe invention is illustrated in more detail by means of the following examples
B e i s ρ i e 1 1B e i s ρ i e 1 1
Eine Lösung von Ig 1-Hyd oxy-S-^A solution of Ig 1-Hydro oxy-S- ^
zo[b,d]pyran-9-on in 25 ml Äthanol wird unter raschem Rühren zu einem Liter Wasser mit einer Temperatur von etwa 25°C gegeben. Nach beend '.er Zugabe der Äthanollösung rührt man etwa 4 Stunden weiter. Es fällt l-Hydroxy-3-(r,r-dimethylheptyI)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-on aus, und der erhaltene Niederschlag wird abfiltriert. Das so hergestellte ausgefällte Dibenzopyranon hat die polymorphe Form mit den oben angegebenen Eigenschaften. Die so hergestellte Form ist mikrokristallin mit einem Teilchengrößenbereich von 2,2 bis 26 μίτι, wobei 50 Volumenprozent eine kleinere Teilchengröße als 7,2 μπι haben.zo [b, d] pyran-9-one in 25 ml of ethanol is added to one liter of water at a temperature of given about 25 ° C. After the addition of the ethanol solution is complete, stirring is continued for about 4 hours. It's falling l-Hydroxy-3- (r, r-dimethylheptyI) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one from, and the precipitate obtained is filtered off. The precipitated dibenzopyranone produced in this way has the polymorphic Shape with the properties given above. The shape so produced is microcrystalline with a range of particle sizes from 2.2 to 26 μm, with 50 volume percent having a particle size smaller than 7.2 μm.
Eine Lösung von Ig l-Hydroxy-S-fr.l'-dimethyiheptylJ-ö.ö-dimethyl-ö.öaJ.S.lO.lOa-hexahydro-gH-dibenzo[b,d]pyran-9-on in 25 ml Äthanol wird in einen Rotationsverdampfer gegeben. Der Verdampferkolben befindet sich in einem auf 20 bis 30° C gehaltenen Wasserbad. Sodann dampft man die Lösung zur Trockne ein, wodurch man das Dibenzopyranon in der polymorphen Form mit den oben angegebenen Eigenschaften erhält.A solution of Ig l-Hydroxy-S-fr.l'-dimethyiheptylJ-ö.ö-dimethyl-ö.öaJ.S.lO.lOa-hexahydro-gH-dibenzo [b, d] pyran-9-one in 25 ml of ethanol is placed in a rotary evaporator. The evaporation flask is located in a water bath kept at 20 to 30 ° C. The solution is then evaporated to dryness, whereby the dibenzopyranone is obtained in the polymorphic form with the properties given above.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41301173A | 1973-11-05 | 1973-11-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE2449927A1 DE2449927A1 (en) | 1975-05-07 |
| DE2449927C2 true DE2449927C2 (en) | 1985-07-04 |
Family
ID=23635422
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2449927A Expired DE2449927C2 (en) | 1973-11-05 | 1974-10-21 | New stable polymorphic crystalline form of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one and a pharmaceutical preparation containing this polymorphic form |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5943463B2 (en) |
| AR (1) | AR202670A1 (en) |
| AT (1) | AT335453B (en) |
| BE (1) | BE821720A (en) |
| BG (1) | BG27088A3 (en) |
| CA (1) | CA1028715A (en) |
| CS (1) | CS174793B2 (en) |
| DD (1) | DD115660A5 (en) |
| DE (1) | DE2449927C2 (en) |
| DK (1) | DK136720B (en) |
| ES (1) | ES431672A1 (en) |
| FR (1) | FR2249665B1 (en) |
| GB (1) | GB1487635A (en) |
| HU (1) | HU167751B (en) |
| IE (1) | IE39678B1 (en) |
| IL (1) | IL45742A (en) |
| NL (1) | NL7412682A (en) |
| PH (1) | PH11719A (en) |
| PL (1) | PL94119B1 (en) |
| RO (1) | RO71769A (en) |
| SE (1) | SE407062B (en) |
| SU (1) | SU611591A3 (en) |
| YU (1) | YU287874A (en) |
| ZA (1) | ZA746029B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4278603A (en) * | 1973-11-05 | 1981-07-14 | Eli Lilly And Company | Novel polymorphic crystalline form of dibenzopyranone |
| US4195078A (en) * | 1979-03-09 | 1980-03-25 | Eli Lilly And Company | Nabilone granulation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3507885A (en) * | 1966-03-25 | 1970-04-21 | Hoffmann La Roche | 3-alkyl-6h-dibenzo(b,d)pyrans |
-
1974
- 1974-09-20 IE IE1949/74A patent/IE39678B1/en unknown
- 1974-09-23 ZA ZA00746029A patent/ZA746029B/en unknown
- 1974-09-25 NL NL7412682A patent/NL7412682A/en not_active Application Discontinuation
- 1974-09-27 IL IL45742A patent/IL45742A/en unknown
- 1974-09-27 PH PH16343A patent/PH11719A/en unknown
- 1974-10-01 CA CA210,510A patent/CA1028715A/en not_active Expired
- 1974-10-05 ES ES431672A patent/ES431672A1/en not_active Expired
- 1974-10-14 SE SE7412921A patent/SE407062B/en unknown
- 1974-10-17 SU SU742069769A patent/SU611591A3/en active
- 1974-10-21 DE DE2449927A patent/DE2449927C2/en not_active Expired
- 1974-10-24 AT AT856674A patent/AT335453B/en not_active IP Right Cessation
- 1974-10-28 YU YU02878/74A patent/YU287874A/en unknown
- 1974-10-31 BE BE150088A patent/BE821720A/en not_active IP Right Cessation
- 1974-10-31 FR FR7436368A patent/FR2249665B1/fr not_active Expired
- 1974-10-31 PL PL1974175276A patent/PL94119B1/pl unknown
- 1974-11-04 DD DD182141A patent/DD115660A5/xx unknown
- 1974-11-04 HU HUEI574A patent/HU167751B/hu unknown
- 1974-11-04 CS CS7516A patent/CS174793B2/cs unknown
- 1974-11-04 GB GB47516/74A patent/GB1487635A/en not_active Expired
- 1974-11-04 DK DK573374AA patent/DK136720B/en not_active IP Right Cessation
- 1974-11-05 RO RO7480429A patent/RO71769A/en unknown
- 1974-11-05 JP JP49127923A patent/JPS5943463B2/en not_active Expired
- 1974-11-05 AR AR256414A patent/AR202670A1/en active
- 1974-11-05 BG BG7428123A patent/BG27088A3/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB1487635A (en) | 1977-10-05 |
| BE821720A (en) | 1975-04-30 |
| BG27088A3 (en) | 1979-08-15 |
| NL7412682A (en) | 1975-05-07 |
| SE407062B (en) | 1979-03-12 |
| DK573374A (en) | 1975-07-07 |
| PH11719A (en) | 1978-05-30 |
| ES431672A1 (en) | 1977-04-16 |
| HU167751B (en) | 1975-12-25 |
| YU287874A (en) | 1984-04-30 |
| JPS5943463B2 (en) | 1984-10-22 |
| DD115660A5 (en) | 1975-10-12 |
| IE39678B1 (en) | 1978-12-06 |
| AR202670A1 (en) | 1975-06-30 |
| FR2249665A1 (en) | 1975-05-30 |
| SU611591A3 (en) | 1978-06-15 |
| DK136720B (en) | 1977-11-14 |
| RO71769A (en) | 1981-09-24 |
| DE2449927A1 (en) | 1975-05-07 |
| IL45742A (en) | 1978-06-15 |
| ATA856674A (en) | 1976-07-15 |
| IL45742A0 (en) | 1974-11-29 |
| CS174793B2 (en) | 1977-04-29 |
| SE7412921L (en) | 1975-05-06 |
| DK136720C (en) | 1978-04-24 |
| FR2249665B1 (en) | 1978-07-21 |
| CA1028715A (en) | 1978-03-28 |
| AT335453B (en) | 1977-03-10 |
| JPS5082222A (en) | 1975-07-03 |
| IE39678L (en) | 1975-05-05 |
| PL94119B1 (en) | 1977-07-30 |
| ZA746029B (en) | 1976-04-28 |
| AU7362674A (en) | 1976-04-01 |
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