EP3640573B1 - Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost - Google Patents

Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost Download PDF

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Publication number
EP3640573B1
EP3640573B1 EP19214972.2A EP19214972A EP3640573B1 EP 3640573 B1 EP3640573 B1 EP 3640573B1 EP 19214972 A EP19214972 A EP 19214972A EP 3640573 B1 EP3640573 B1 EP 3640573B1
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Prior art keywords
chamber
product
pressure
condensing chamber
nucleation
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English (en)
French (fr)
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EP3640573A1 (de
Inventor
Weijia LING
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Millrock Technology Inc
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Millrock Technology Inc
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Priority claimed from US14/205,802 external-priority patent/US9435586B2/en
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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 method of controlling nucleation during the freezing step of a freeze drying cycle and, more particularity, to such a method that uses a pressure differential ice fog distribution to trigger a spontaneous nucleation among all vials in a freeze drying apparatus at a predetermined nucleation temperature.
  • US 2014/041250 A1 discloses a method of controlling and enhancing nucleation of a product in a freeze dryer according to the prior art.
  • the range of nucleation temperatures across the vials is distributed randomly between a temperature near the thermodynamic freezing temperature and some value significantly (e.g., up to about 30°C.) lower than the thermodynamic freezing temperature.
  • This distribution of nucleation temperatures causes vial-to-vial variation in ice crystal structure and ultimately the physical properties of the lyophilized product.
  • the drying stage of the freeze- drying process must be excessively long to accommodate the range of ice crystal sizes and structures produced by the natural stochastic nucleation phenomenon.
  • Nucleation is the onset of a phase transition in a small region of a material.
  • the phase transition can be the formation of a crystal from a liquid.
  • the crystallization process i.e., formation of solid crystals from a solution
  • the crystallization process i.e., formation of solid crystals from a solution
  • Ice crystals can themselves act as nucleating agents for ice formation in sub-cooled aqueous solutions.
  • a humid freeze- dryer is filled with a cold gas to produce a vapor suspension of small ice particles.
  • the ice particles are transported into the vials and initiate nucleation when they contact the fluid interface.
  • the currently used "ice fog” methods do not control the nucleation of multiple vials simultaneously at a controlled time and temperature.
  • the nucleation event does not occur concurrently or instantaneously within all vials upon introduction of the cold vapor into the freeze-dryer.
  • the ice crystals will take some time to work their way into each of the vials to initiate nucleation, and transport times are likely to be different for vials in different locations within the freeze-dryer.
  • implementation of the "ice fog” method would require system design changes as internal convection devices may be required to assist a more uniform distribution of the "ice fog" throughout the freeze-dryer.
  • freeze-dryer shelves are continually cooled, the time difference between when the first vial freezes and the last vial freezes will create a temperature difference between the vials, which will increase the vial-to- vial non-uniformity in freeze-dried products.
  • the method of the present invention meets this need.
  • the invention is defined by the method according to claim 1.
  • an ice fog is not formed inside the product chamber by the introduction of a cold gas, e.g., liquid nitrogen chilled gas at -196°C, which utilizes the humidity inside the product chamber to produce the suspension of small ice particles in accordance with known methods in the prior art.
  • a cold gas e.g., liquid nitrogen chilled gas at -196°C
  • These known methods have resulted in increased nucleation time, reduced uniformity of the product in different vials in a freeze drying apparatus, and increased expense and complexity because of the required nitrogen gas chilling apparatus.
  • My related invention disclosed in pending Patent Application Serial No. 13/097,219 filed on April 29, 2012 utilizes the pressure differential between the product chamber and a condenser chamber to instantly distribute ice nucleation seeding to trigger controlled ice nucleation in the freeze dryer product chamber.
  • the nucleation seeding is generated in the condenser chamber by injecting moisture into the cold condenser. The moisture is injected by releasing vacuum and injecting the moisture into the air entering the condenser. The injected moisture freezes into tiny suspended ice crystals (ice fog) in the condenser chamber.
  • the condenser pressure is close to atmosphere, while the product chamber is at a reduced pressure. With the opening of an isolation valve between the chambers, the nucleation seeding in the condenser is injected into the product chamber within several seconds. The nucleation seeding evenly distributes among the super cooled product triggering controlled ice nucleation.
  • the larger ice crystals help to achieve consistent nucleation coverage and greatly improve controlled nucleation performance, especially when the product chamber has restriction in gas flow. such as side plates or when the vapor port is located under or above the shelf stack.
  • the volume of suspended ice fog in gas form was limited by the condenser volume.
  • the thickness of frost can easily be controlled to achieve a desired density of larger ice crystals in the product chamber during nucleation.
  • the condensed frost method works with any condensing surface.
  • the size of the condensing chamber may be reduced to increase the velocity of the gas in the condenser.
  • an apparatus 10 for performing the method of the present invention comprises a freeze dryer 12 having one or more shelves 14 for supporting vials of product to be freeze dried.
  • a condenser chamber 16 is connected to the freeze dryer 12 by a vapor port 18 having an isolation valve 20 of any suitable construction between the condenser chamber 16 and the freeze dryer 12.
  • the isolation valve 20 is constructed to seal vacuum both ways.
  • a vacuum pump 22 is connected to the condenser chamber 16 with a valve 21 therebetween of any suitable construction.
  • the condenser chamber 16 has a fill valve 24 and a vent valve 27 and filter 28 of any suitable construction and the freeze dryer 12 has a control valve 25 and release valve 26 of any suitable construction.
  • the operation of the apparatus 10 in accordance with one embodiment of the method of the present invention is as follows:
  • Figure 2 illustrates a compact condenser 100 connected to a freeze dryer 102 having an internal condenser 104 which is not constructed to produce condensed frost therein and requires an additional seeding chamber and related hardware to be added.
  • the freeze dryer 102 comprises a product chamber 106 with shelves 108 therein for supporting the product to be freeze dried.
  • the compact condenser 100 comprises a nucleation seeding generation chamber 110 having a cold surface or surfaces 112 defining frost condensing surfaces.
  • the cold surface 112 may be a coil, plate, wall or any suitable shape to provide a large amount of frost condensing surface in the nucleation seeding generation chamber 110 of the compact condenser 100.
  • a moisture injection nozzle 1 14 extends into the nucleation seeding generation chamber 110 and is provided with a moisture injection or fill valve 116.
  • a venting gas supply line 118 having a filter 120 is connected to the nucleation seeding generation chamber 110 by a vacuum release or vent valve 122.
  • the nucleation seeding generation chamber 110 of the compact condenser 100 is connected to the freeze dryer 102 by a nucleation valve 124.
  • the flow of gas and moisture into the nucleation seeding generation chamber 110 produces condensed frost on the surfaces of the concentric coils, plates, walls or other surfaces 112. Since the pressure in the compact condenser 100 is greater than that in the freeze dryer 102, when the nucleation valve 124 and vent valve 122 are opened, strong gas turbulence is created in the nucleation seeding generation chamber 110 to remove loosely condensed frost on the inner surfaces of the coils, plates, walls or other surfaces 112 therein and to break it into ice crystals that mix in the gas flow rushing into the product chamber 106 to increase the effectiveness of the nucleation process in the product chamber.
  • Figure 3 illustrates a compact condenser 200 connected to a freeze dryer 202 having an external condenser 204.
  • the construction and operation of the compact condenser 200 is the same as that of the compact condenser 100 shown in Figure 2 .
  • This method of nucleation is unique by combining an external controllable pre-formation of condensed frost with a sudden pressure differential distribution method. This results in a rapid nucleation event because of the large ice crystals, taking seconds instead of minutes, no matter what size of system it is used on. It gives the user precise control of the time and temperature of nucleation and has the following additional advantages:
  • the novel method of the present invention produces a condensed frost in a condenser chamber external to the product chamber in a freeze dryer and then, as a result of gas turbulence, rapidly introduces ice crystals into the product chamber which is at a pressure lower than the pressure in the condenser chamber.
  • This method produces rapid and uniform nucleation of the product in different vials of the freeze dryer.

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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)
  • Drying Of Solid Materials (AREA)

Claims (8)

  1. Verfahren zur Steuerung und Verbesserung der Nukleierung eines Produkts in einem Gefriertrockner, Folgendes umfassend:
    Halten des Produkts bei einer festgelegten Temperatur und einem festgelegten Druck in einer Produktkammer des Gefriertrockners;
    Erzeugen eines festgelegten Volumens von kondensiertem Frost auf einer Innenfläche einer Kondensierkammer, die von der Produktkammer getrennt ist, wobei die Kondensierkammer über einen Dampfanschluss mit der Produktkammer verbunden ist, wobei ein festgelegtes befeuchtetes Füllgas in die Kondensierkammer eingeleitet wird, um den kondensierten Frost herzustellen, während die Kondensierkammer Umgebungsdruck hat; und
    wenn der Druck in der Kondensierkammer einen festgelegten Druck aufweist, der größer als der der Produktkammer ist, Erzeugen von Gasturbulenzen, die den kondensierten Frost in Eiskristalle aufbrechen, die schnell in die Produktkammer eintreten, um sich gleichmäßig darin zu verteilen und eine gleichförmige und schnelle Nukleierung des Produkts in verschiedenen Bereichen der Produktkammer zu erzeugen.
  2. Verfahren nach Anspruch 1, wobei die Gasturbulenzen durch Öffnen des Dampfanschlusses in die Produktkammer erzeugt werden, wenn die Kondensierkammer den festgelegten Druck aufweist.
  3. Verfahren nach Anspruch 1, wobei der Dampfanschluss zwischen der Produktkammer und der Kondensierkammer ein Sperrventil aufweist, um den Dampfstrom dazwischen zu öffnen oder zu schließen.
  4. Verfahren nach Anspruch 3, wobei eine Vakuumpumpe mit der Kondensierkammer verbunden ist, um den Druck innerhalb der Produktkammer und der Kondensierkammer zu verringern.
  5. Verfahren nach Anspruch 1, wobei der Druck in der Produktkammer etwa 50 Torr beträgt und der Druck in der Kondensierkammer in etwa Umgebungsdruck hat, wenn der Dampfanschluss in die Produktkammer geöffnet ist.
  6. Verfahren nach Anspruch 1, wobei die Temperatur des Produkts etwa -5,0 °C beträgt und die Temperatur der Kondensierkammer weniger als 0 °C beträgt.
  7. Verfahren nach Anspruch 1, wobei die Kondensierkammer ein Füllventil aufweist, das geöffnet wird, um zuzulassen, dass das befeuchtete Füllgas in die Kondensierkammer eingeleitet wird, um den kondensierten Frost herzustellen, wobei das Füllgas gefilterte Umgebungsluft ist und einen Feuchtigkeitsgehalt von 50-80 Volumenprozent aufweist und wobei das Füllgas Stickstoff oder Argon mit hinzugefügter Feuchtigkeit ist.
  8. Verfahren nach Anspruch 1, wobei die Innenfläche der Kondensierkammer durch mehrere innere Windungen, Platten oder Wände definiert ist, wobei die Innenwände eine Windungsanordnung aufweisen, um die Größe der Innenfläche zu maximieren.
EP19214972.2A 2014-03-12 2014-09-18 Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost Active EP3640573B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14/205,802 US9435586B2 (en) 2012-08-13 2014-03-12 Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice crystals distribution from condensed frost
EP14885084.5A EP3117165B1 (de) 2014-03-12 2014-09-18 Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost
PCT/US2014/056192 WO2015138005A1 (en) 2014-03-12 2014-09-18 Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice crystals distribution from condensed frost

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP14885084.5A Division-Into EP3117165B1 (de) 2014-03-12 2014-09-18 Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost
EP14885084.5A Division EP3117165B1 (de) 2014-03-12 2014-09-18 Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost

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EP3640573A1 EP3640573A1 (de) 2020-04-22
EP3640573B1 true EP3640573B1 (de) 2024-05-22

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EP14885084.5A Active EP3117165B1 (de) 2014-03-12 2014-09-18 Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost
EP19214972.2A Active EP3640573B1 (de) 2014-03-12 2014-09-18 Kontrollierte nukleierung während des gefrierschrittes eines gefriertrocknungszyklus mittels differenzieller eiskristallverteilung von kondensiertem frost

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EP (2) EP3117165B1 (de)
JP (1) JP6389270B2 (de)
CN (2) CN110108097A (de)
ES (1) ES2799600T3 (de)
WO (1) WO2015138005A1 (de)

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JP6389270B2 (ja) * 2014-03-12 2018-09-12 ミルロック テクノロジー, インコーポレイテッドMillrock Technology, Inc. 凝縮した霜から発生させた氷晶の、圧力差による分布を用いた凍結乾燥サイクルの凍結ステップにおける制御された核形成
SI3392584T1 (sl) 2017-04-21 2020-09-30 Gea Lyophil Gmbh Zamrzovalni sušilnik in postopek za induciranje nukleacije v proizvodih
WO2022175999A1 (ja) 2021-02-16 2022-08-25 株式会社アルバック 凍結乾燥装置、および凍結乾燥方法

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US4350568A (en) * 1981-04-15 1982-09-21 Dalupan Romulo V High efficiency water distillation apparatus
EP1563237A2 (de) * 2002-11-21 2005-08-17 Transform Pharmaceuticals, Inc. Gefriertrocknungsmikroskopstufenvorrichtung undverwendungsverfahren daf r
CN101379356B (zh) * 2006-02-10 2013-07-17 普莱克斯技术有限公司 诱导材料成核的方法
US8240065B2 (en) * 2007-02-05 2012-08-14 Praxair Technology, Inc. Freeze-dryer and method of controlling the same
US20110179667A1 (en) * 2009-09-17 2011-07-28 Lee Ron C Freeze drying system
US8549768B2 (en) * 2011-03-11 2013-10-08 Linde Aktiengesellschaft Methods for freeze drying
US8839528B2 (en) * 2011-04-29 2014-09-23 Millrock Technology, Inc. Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice fog distribution
US8875413B2 (en) * 2012-08-13 2014-11-04 Millrock Technology, Inc. Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice crystals distribution from condensed frost
JP6389270B2 (ja) * 2014-03-12 2018-09-12 ミルロック テクノロジー, インコーポレイテッドMillrock Technology, Inc. 凝縮した霜から発生させた氷晶の、圧力差による分布を用いた凍結乾燥サイクルの凍結ステップにおける制御された核形成

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CN106255860A (zh) 2016-12-21
EP3117165B1 (de) 2020-03-25
CN106255860B (zh) 2019-06-18
WO2015138005A1 (en) 2015-09-17
ES2799600T3 (es) 2020-12-18
JP6389270B2 (ja) 2018-09-12
JP2017508126A (ja) 2017-03-23
EP3640573A1 (de) 2020-04-22
EP3117165A1 (de) 2017-01-18
CN110108097A (zh) 2019-08-09
EP3117165A4 (de) 2017-11-22

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