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EP1206670B1 - Procede de lyophilisation - Google Patents

Procede de lyophilisation Download PDF

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Publication number
EP1206670B1
EP1206670B1 EP00954556A EP00954556A EP1206670B1 EP 1206670 B1 EP1206670 B1 EP 1206670B1 EP 00954556 A EP00954556 A EP 00954556A EP 00954556 A EP00954556 A EP 00954556A EP 1206670 B1 EP1206670 B1 EP 1206670B1
Authority
EP
European Patent Office
Prior art keywords
drying
temperature
phase
solvent
pressure
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 - Lifetime
Application number
EP00954556A
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German (de)
English (en)
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EP1206670A1 (fr
Inventor
Bernd Sennhenn
Martin Kramer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
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Bayer Healthcare AG
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Publication date
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Publication of EP1206670A1 publication Critical patent/EP1206670A1/fr
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Publication of EP1206670B1 publication Critical patent/EP1206670B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • the present invention relates to a novel process for freeze-drying (Lyophilization).
  • Freeze-drying is an important stabilization process hydrolysis-sensitive and thermolabile preparations, as well as materials of biological origin, which are dried under mild conditions should. With the help of freeze-drying materials can be used without major Changes and losses of biological activity are dried.
  • One positive aspect of freeze-drying is that the dried, "lyophilic" Products due to their porous structure and very large specific surface area are very quickly reconstituted and their original properties in solution accept again. Therefore, freeze drying is preferred therapeutic sera, blood products, biologically active substances (hormones, Vitamins, enzymes, medicines), food preparations and flavorings.
  • Freeze-drying liquid and semi-solid water-containing preparations are suitable, e.g. Solutions, emulsions and suspensions.
  • the two drying steps differ in principle: In the Primary drying (primary drying) is the sublimation of the frozen Solvent under reduced pressure. At optional drying (Secondary drying), the evaporation of non-frozen solvent at reduced pressure and at elevated temperature.
  • the method to be dried Preparations in containers, e.g. so-called vials, frozen at atmospheric pressure and The temperature of the product is set to one for the start of the main drying appropriate value set.
  • the freezing is followed by the main drying, in which, under reduced pressure, the frozen solvent is transferred from the solid to the gaseous state, ie sublimed.
  • the energy that is consumed in the sublimation is replenished, for example, via heatable control panels.
  • the frozen preparation must not heat above its melting point.
  • the main drying can be followed by a final drying, in which non-frozen solvent is removed at elevated temperature and reduced pressure.
  • non-frozen solvent is removed at elevated temperature and reduced pressure.
  • the temperature profile during the freeze-drying can be controlled by suitable devices.
  • temperature-controlled control panels are known to those skilled in the art. In this process, the control panels can be brought to the desired glass transition temperature both after loading (cooling variant A) and before loading (cooling variant B). It is also possible to pre-temper the plates and / or the preparation on the plates to a temperature above the actual glass transition temperature to ensure a temperature equalization of the individual vials, or to minimize the cooling time to freezing. This is followed by the actual freezing with further lowering of the plate temperature (cooling variant C).
  • the variants AC describe the freezing on shelves.
  • Other known methods are freezing methods in cold baths and rotating vessels (shell freezing, spin freezing) or by spraying devices; they differ in principle from the methods described above.
  • the preparations to be dried are aqueous systems.
  • other solvents or mixtures thereof with aqueous systems can be used, such as carboxylic acids (eg glacial acetic acid), dimethyl sulfoxide (DMSO), ethers (eg dioxane), dimethylformamide or alcohols (eg t-butanol).
  • US 3,233,333 describes a process for freeze-drying of meat and other foods that contain cellular structures, but by performing in four steps, the physical quality is not is impaired and taste, smell and texture practically remain unchanged.
  • a tempering step thermal treatment or annealing
  • This annealing step serves to crystallize amorphous solidified solids and not to require frozen solvent and thus increased crystallinity and to achieve a reduced residual moisture.
  • Tg ' Glass transition temperature
  • the amorphous phase which usually contains high levels of contains uncrystallized solvent, goes from the glass state in the rubbery Condition over and the mobility of molecules is increased. Consequence is the Formation of nucleoli that grow into crystals (so-called eruptive recrystallization) and the attachment of solvent molecules to existing ones Solvent crystals.
  • the annealing process is also known from the literature. Descriptions of the tempering process can be found in The Lyophilization of Pharmaceuticals: A Literature Review, NA Williams and GP Polli, Journal of Parenteral Science and Technology, (1984 Mar-Apr) 38 (2) 48-59, Basic Aspects and Future Trends in the Freeze Drying of Pharmaceuticals , L. Rey, Develop. biol. Standard, Vol. 74, (Karger, Basel, 1991), pp. 3-8 and Fundamental Aspects of Lyophilization, L. Rey, Research and Development in Freeze-Drying, ed. By L. Rey, Paris, 1964, 24-47.
  • Lyophilisates usually have a high flow resistance, which is the Escape of the gaseous solvent impeded.
  • the consequences, the This may result in mechanical damage to the product cake by the escaping solvent vapor stream and thereby potential Product loss, as well as collapse and thawing phenomena during drying.
  • by the end user especially to pharmaceutical and Food preparations also made aesthetic demands, so that strong Damage is not desired.
  • An object of the present invention was therefore a process for freeze-drying to find, with which lyophilizates can be produced, which are the above do not exhibit said problematic properties and therefore easier are manageable.
  • the fixed point of the preparation in the present application is the one Temperature understood in which the solvent in the preparation in the solid State of aggregation passes.
  • This pressure reduction can e.g. be carried out at room temperature.
  • the preparations are before or during the Lowering the pressure to a temperature between room temperature and the Fixed point of the preparation is, pre-tempered.
  • This pre-tempering e.g. Stellplatten
  • This pre-tempering further ensures that the cooling devices, the z.T. low Have cooling rates, in a short time to the desired crystallization temperature, i.e. can be brought into the range of the fixed point of the preparation. critical is that this Vortemper réelle not for the crystallization of the solvent leads.
  • the pressure in the Drying chamber raised to ambient pressure and the temperature in the drying chamber for crystallization at or below the fixed point of Preparation (phase 2). It is also possible the pressure during to keep the crystallization reduced; this has no relevant effects the crystallization of the solvent.
  • every crystallization is Temperature suitable, which is below the benchmark of the preparation or with him is identical.
  • the temperature is Crystallization in aqueous solutions between -60 ° C and 0 ° C.
  • the preparation is optionally to the final Temperature brought to the beginning of drying.
  • This temperature is from the present product and the vapor pressure curve of the solvent from Pressure to be used in the main drying depends. In a preferred embodiment, this temperature is in aqueous solutions -60 ° C to 0 ° C.
  • phase 4 a post-drying phase following the Main drying on.
  • phase 4a an annealing phase
  • an annealing process such as connected above. This annealing process is referred to as Phase 2a referred. Annealing provides products with higher crystallinity and lower residual moisture after the main drying and shortens the post-drying or makes them redundant.
  • Fig. 2 shows a conventional manufacturing method of the prior art.
  • FIG. 3 shows a conventional manufacturing process with annealing step after State of the art.
  • phase 4 shows the method according to the invention with pressure reduction (phase 1), Crystallization (phase 2), annealing step (phase 2a) and subsequent main and Post-drying (phases 3 and 4).
  • phase 5 shows the method according to the invention with pre-tempering and pressure reduction (Phase 1), crystallization (phase 2) and subsequent main and Post-drying (phases 3 and 4).
  • Fig. 6 shows the inventive method with pre-tempering and Pressure reduction (phase 1), crystallization (phase 2), annealing step (phase 2a) and subsequent main and post-drying (phases 3 and 4).
  • phase 7 shows the method according to the invention with pressure reduction (phase 1), Crystallization (phase 2), followed by main and post-drying (phases 3 and 4).
  • the lyophilizates which can be prepared by the process according to the invention have a improved structure cohesion and are escaping from the Steam flow, even at increased sublimation rates, less mechanically strong damaged as lyophilisates by methods of the prior art getting produced. They show less pronounced collapse phenomena.
  • Preparations with or without so-called scaffold formers are suitable for use in the process according to the invention.
  • a porous scaffold or a matrix can be produced during freeze-drying.
  • Freeze-drying products which are prepared using scaffold formers or other substances which are suitable as scaffolding agents on account of their physicochemical properties are preferred.
  • Particularly preferred are freeze-drying products which are prepared using skeleton formers selected from the classes of compounds amino acids, carbohydrates (mono-, disaccharides, sugar alcohols, oligosaccharides, polysaccharides), peptides, polymeric compounds and salts.
  • skeleton formers selected from the classes of compounds amino acids, carbohydrates (mono-, disaccharides, sugar alcohols, oligosaccharides, polysaccharides), peptides, polymeric compounds and salts.
  • Most preferred are those prepared using frameworks selected from the group consisting of mannitol, sucrose, maltose, glycine and sodium chloride.

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  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Drying Of Solid Materials (AREA)
  • Freezing, Cooling And Drying Of Foods (AREA)

Claims (9)

  1. Procédé de lyophilisation de préparations dans une chambre de dessiccation, comprenant les étapes de refroidissement de la préparation et cristallisation ainsi que sublimation sous pression réduite du solvant congelé, le procédé étant mis en oeuvre de la façon suivante :
    phase 1 :
    abaissement de la pression dans la chambre de dessiccation jusqu'à l'apparition d'une cristallisation visible du solvant à une température, dans la chambre de dessiccation, qui se trouve au-dessus du point de solidification de la préparation,
    phase 2 :
    abaissement de la température, dans la chambre de dessiccation, à une valeur qui est inférieure ou identique au point de solidification de la préparation, jusqu'à la fin de la cristallisation du solvant,
    phase 3 :
    sublimation sous pression réduite du solvant congelé.
  2. Procédé suivant la revendication 1, caractérisé par la présence d'une solution aqueuse.
  3. Procédé suivant la revendication 1, caractérisé en ce que la pression dans la phase 1 est abaissée à une valeur de 0,1 à 6 mbar dans le cas de préparations aqueuses.
  4. Procédé suivant la revendication 3, caractérisé en ce que la pression dans la phase 1 est abaissée à une valeur de 0,2 à 3 mbar.
  5. Procédé suivant la revendication 1, caractérisé en ce que la température dans la phase 2 est réglée à une valeur de -60 à 0°C dans le cas de préparations aqueuses.
  6. Procédé suivant la revendication 1, caractérisé par une étape d'équilibrage de température (2a) dans laquelle est réglée une température qui est au-dessus de la température de transition vitreuse (Tg') de la solution à l'état solidifié amorphe et en dessous du point de solidification de la préparation.
  7. Procédé suivant la revendication 1, caractérisé en ce que la température au début de la dessiccation principale est réglée à une valeur de -60 à 0°C dans le cas de préparations aqueuses.
  8. Procédé suivant la revendication 1, caractérisé en ce qu'une substance de structuration est utilisée.
  9. Procédé suivant la revendication 1, caractérisé en ce qu'on utilise comme substance de structuration le mannitol, le saccharose, le maltose, la glycine ou le chlorure de sodium.
EP00954556A 1999-08-02 2000-07-21 Procede de lyophilisation Expired - Lifetime EP1206670B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19936281 1999-08-02
DE19936281A DE19936281C2 (de) 1999-08-02 1999-08-02 Verfahren zur Gefriertrocknung
PCT/EP2000/007034 WO2001009559A1 (fr) 1999-08-02 2000-07-21 Procede de lyophilisation

Publications (2)

Publication Number Publication Date
EP1206670A1 EP1206670A1 (fr) 2002-05-22
EP1206670B1 true EP1206670B1 (fr) 2005-02-09

Family

ID=7916878

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00954556A Expired - Lifetime EP1206670B1 (fr) 1999-08-02 2000-07-21 Procede de lyophilisation

Country Status (8)

Country Link
US (1) US6684524B1 (fr)
EP (1) EP1206670B1 (fr)
JP (1) JP2003506654A (fr)
AU (1) AU6697200A (fr)
CA (1) CA2380949A1 (fr)
DE (2) DE19936281C2 (fr)
ES (1) ES2237445T3 (fr)
WO (1) WO2001009559A1 (fr)

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DE10058119A1 (de) 2000-11-22 2002-05-23 Bayer Ag Pepinotan-Kit
FR2836482B1 (fr) * 2002-02-25 2005-02-11 Zedrys Zeolite Drying System Procede et installations pour l'obtention de cellules vivantes dessechees
KR20060052880A (ko) * 2003-07-25 2006-05-19 와이어쓰 동결건조된 ｃｃｉ- 779 제형
US8793895B2 (en) * 2006-02-10 2014-08-05 Praxair Technology, Inc. Lyophilization system and method
US9453675B2 (en) 2006-02-10 2016-09-27 Sp Industries, Inc. Method of inducing nucleation of a material
US8820097B2 (en) 2006-02-10 2014-09-02 Praxair, Technology, Inc. Method and system for regulating the mixture of cryogen liquid and warm gas for a controlled rate cryogenic chiller or freezing system
US8794013B2 (en) 2006-02-10 2014-08-05 Praxair Technology, Inc. Method and system for nucleation control in a controlled rate freezer (CRF)
EP1870649A1 (fr) * 2006-06-20 2007-12-26 Octapharma AG Lyophilisation visant à obtenir une humidité résiduelle déterminée par énergie de désorption aux niveaux limités
MX2009003389A (es) * 2006-10-03 2009-04-09 Wyeth Corp Metodos y aparatos de liofilizacion.
US8240065B2 (en) 2007-02-05 2012-08-14 Praxair Technology, Inc. Freeze-dryer and method of controlling the same
FR2923823B1 (fr) * 2007-11-21 2010-10-08 Centre Nat Rech Scient Aerogels de nanotubes de carbone
EP2329005A4 (fr) * 2008-09-12 2011-10-12 Enwave Corp Appareil et procédé de déshydratation de matières biologiques par congélation et micro-ondes
CN101718485B (zh) * 2009-11-25 2013-02-06 天津商业大学 近冻结温度干燥或浓缩的方法所使用设备
WO2011067780A1 (fr) 2009-12-02 2011-06-09 Central Pollution Control Board Appareil et procédé de préservation de peaux/cuirs d'animaux
US8549768B2 (en) * 2011-03-11 2013-10-08 Linde Aktiengesellschaft Methods for freeze drying
RU2480520C1 (ru) * 2011-10-03 2013-04-27 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования Воронежская государственная технологическая академия (ФГБОУ ВПО ВГТА) Способ управления процессами получения и сушки ферментных препаратов
IN2013MU01127A (fr) 2013-03-26 2015-05-01 Astron Res Ltd
CN104697298B (zh) * 2015-03-13 2016-12-07 湖南科伦制药有限公司 一种水溶性维生素的冻干工艺
EP3411499B1 (fr) 2016-02-05 2023-11-08 Gen-Probe Incorporated Compositions d'amplification séchées
DE102016215844B4 (de) 2016-08-23 2018-03-29 OPTIMA pharma GmbH Verfahren und Vorrichtung zur Gefriertrocknung
EP4491721A3 (fr) 2017-05-19 2025-03-05 Gen-Probe Incorporated Compositions séchées contenant une endonucléase flap
DE102017217415B4 (de) 2017-09-29 2022-11-10 OPTIMA pharma GmbH Verfahren und Vorrichtung zur Gefriertrocknung
CA3113007A1 (fr) 2018-09-26 2020-04-02 Medac Gesellschaft Fur Klinische Spezialpraparate Mbh Forme cristalline de treosulfan
PT3856151T (pt) * 2018-09-26 2023-10-27 Medac Ges Fuer Klinische Spezialpraeparate Mbh Liofilizado de treossulfano
US11744257B1 (en) * 2018-10-19 2023-09-05 Harvest Right, LLC Freeze-drying methods including vacuum freezing
US12225914B1 (en) 2023-05-08 2025-02-18 Harvest Right, LLC Freeze dryers and drying processes for materials with low water content

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Also Published As

Publication number Publication date
WO2001009559A1 (fr) 2001-02-08
US6684524B1 (en) 2004-02-03
DE50009496D1 (de) 2005-03-17
AU6697200A (en) 2001-02-19
DE19936281C2 (de) 2002-04-04
DE19936281A1 (de) 2001-02-15
EP1206670A1 (fr) 2002-05-22
CA2380949A1 (fr) 2001-02-08
JP2003506654A (ja) 2003-02-18
ES2237445T3 (es) 2005-08-01

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