JP6389270B2 - Controlled nucleation in the freezing step of a freeze-drying cycle using the pressure difference distribution of ice crystals generated from condensed frost - Google Patents

Description

  This application is a continuation-in-part of US patent application Ser. No. 13 / 572,978, filed Aug. 13, 2012, the entire contents of which are hereby incorporated by reference.

  The present invention relates to a method for controlling nucleation in a freezing step of a freeze-drying cycle. More particularly, the present invention relates to a method of inducing spontaneous nucleation in all vials (vials) in a freeze-drying apparatus at a predetermined nucleation temperature by using ice mist distribution due to pressure difference.

  There is a strong need in the art to control a generally random nucleation process during the vacuum freeze drying process or the freezing stage of the freeze drying process. The purpose of the control is to reduce the processing time required to complete lyophilization and to improve the uniformity in the final product from vial to vial. In a typical lyophilization process, multiple vials containing a common aqueous solution are placed on a shelf and cooled to a low temperature, typically at a controlled cooling rate. This aqueous solution in each vial is cooled below the thermodynamic freezing point of the solution and remains in a sub-cooled, metastable liquid state until nucleation occurs.

  The nucleation temperature range for each vial is randomly distributed between the vicinity of the thermodynamic freezing point and a temperature that is somewhat significantly lower (eg up to about 30 ° C.) from the thermodynamic freezing point. This distribution of nucleation temperatures causes variations in ice crystal structure from vial to vial, and ultimately variations in the physical properties of the freeze-dried product. Furthermore, the drying stage of the lyophilization process must take an excessively long time to adjust the range of ice crystal size and structure produced by the normal probability nucleation phenomenon.

  Nucleation is the beginning of a phase transition in a microregion of matter. For example, the phase transition can be the formation of crystals from a liquid. The crystallization process often associated with solution freezing (ie, the formation of solid crystals from solution) is initiated by a nucleation event prior to crystal growth.

  Ice crystals can act as a nucleating agent that forms ice in an aqueous solution that is itself supercooled. In the known “ice fog” process, a high humidity freeze dryer is filled with a cold gas to produce a vapor suspension of small ice particles. The ice particles move into the vial and contact the fluid surface to initiate nucleation.

  Currently used “ice fog” methods do not control multiple vials to nucleate simultaneously at a controlled time and temperature. In other words, nucleation events do not occur simultaneously or instantaneously in all vials when introducing cold steam into the lyophilizer. Ice crystals travel through each vial and take some time to begin nucleation. And the travel time will vary depending on the location of the vial in the freeze dryer. In large industrial freeze dryers, system design changes may be required to implement the “ice fog” method. This is because a convection device may need to be provided inside in order to more uniformly distribute “ice mist” in the entire freeze dryer. If the lyophilizer shelf is continuously cooled, the time difference between the first vial being frozen and the last vial freezing results in a temperature difference between the vials. This temperature difference increases the non-uniformity from vial to vial in the lyophilized product.

  Accordingly, a need has arisen for a method that results in a more rapid and uniform freezing of the aqueous solution in all vials in the lyophilizer. The method of the present invention satisfies this need.

  In the new and improved method of the present invention, ice mist is not formed when a cold gas (eg, a gas cooled to -196 ° C. with liquid nitrogen) is introduced inside the production chamber. The method uses the humidity inside the production chamber to produce a suspension of small ice particles according to methods known in the prior art. These known methods result in increased nucleation time, reduced product uniformity in different vials within the lyophilizer, and increased cost and complexity due to the need for a nitrogen gas chiller. It was done.

  Applicant's related invention disclosed in pending patent application No. 13 / 097,219 (filed April 29, 2012) utilizes the pressure difference between the production chamber and the condensation chamber. . This instantly distributes ice nucleation species and initiates controlled ice nucleation in the production chamber of the lyophilization chamber.

  Nucleating species are generated in the condenser by injecting moisture into the cold condenser. Moisture is injected by releasing the vacuum and injecting moisture into the air flowing into the condenser. The injected moisture freezes in the condensation chamber and becomes fine ice crystals (ice mist) that float. The pressure of the condenser is close to atmospheric pressure. On the other hand, the pressure in the production chamber is reduced. By opening the shutoff valve between these chambers, the nucleating species in the condenser are injected into the production chamber within a few seconds. Nucleating species are evenly distributed in the supercooled product and initiate controlled ice nucleation.

  It has already been found that when the shut-off valve is opened, a sudden change in pressure causes strong gas turbulence in the condensation chamber. This turbulent flow can dispel any frost that has been gently condensed on the condensing surface, causing the frost to become larger ice crystals. Larger ice crystals separate from the condensing surface and mix with the gas stream entering the production chamber. The larger the ice crystal size, the longer it can remain in the production chamber, which can be more effective in the nucleation process.

  Larger ice crystals help achieve consistent nucleation coverage and significantly improve controlled nucleation performance. In particular, if the gas flow in the production chamber is restricted (such as by a side plate) or if the vapor port is located below or above the shelf stack, the ice crystals can be of great help.

  Until now, the volume of ice mist floating in the gaseous state has been limited by the volume of the condenser. By adding high density frost to the condensation surface, the physical volume of the condenser is no longer limited. In order to achieve larger ice crystals of the desired density, the frost thickness can be easily controlled in the production chamber during nucleation. The condensed frost method can be performed on any condensing surface. In addition, the size of the condensation chamber may be reduced to increase the velocity of the gas in the condenser.

FIG. 1 is a schematic diagram illustrating one embodiment of an apparatus for performing the method of the present invention. FIG. 2 is a schematic view showing a second embodiment of an apparatus for carrying out the method of the present invention, wherein the apparatus is connected to a freeze dryer having a condenser inside. FIG. 3 is a schematic view showing a second embodiment of the apparatus for executing the method of the present invention, in which the apparatus is connected to a freeze dryer having a condenser outside.

  As shown in FIG. 1, an apparatus 10 for carrying out the method of the present invention includes a freeze dryer 12. The lyophilizer 12 has one or more shelves 14 for holding vials of product to be lyophilized. The condensation chamber 16 is connected to the lyophilizer 12 via a vapor port 18. The vapor port 18 has a shutoff valve 20 of any suitable configuration between the condensation chamber 16 and the lyophilizer 12. Preferably, the shutoff valve 20 is configured to seal the vacuum on both sides.

  The vacuum pump 22 is connected to the condensation chamber 16. Between the vacuum pump 22 and the condensation chamber 16, a valve 21 having any suitable configuration is provided. The condensation chamber 16 has a fill valve 24 and a ventilation valve 27 and a filter 28 having any suitable structure. The freeze dryer 12 has a control valve 25 and a release valve 26 of any suitable structure.

  As an illustrative example, the operation of the apparatus 10 according to one embodiment of the method of the present invention is as follows.

  1. For nucleation, shelf 14 is cooled to a preselected temperature (e.g., -5 <0> C) below the freezing point of water sufficient to supercool the product.

  2. The shelf temperature is maintained until the detected temperature of all products is very close to the shelf temperature (eg, within 0.5 ° C.).

  3. Maintain an additional 10-20 minutes so that the temperature of all vials (not shown) is more uniform.

  4). With the shutoff valve 20 open, the valve 21 is opened and the vacuum pump 22 is driven. A vacuum pump 22 pumps down to the pressure of the chamber 13 and the condensation chamber 16 in the freeze dryer 12. The reduced pressure (for example, 50 Torr) is maintained at a pressure higher than the vapor pressure of water at the product temperature, and bubble formation is prevented.

  5. The shutoff valve 20 between the generation chamber 13 and the condensation chamber 16 is closed, and the valve 21 is closed.

  6). Make sure that the condenser temperature is already at the lowest value (usually -53 ° C or -85 ° C).

  7). The filling valve 24 is opened, and the filling gas containing moisture is slowly filled into the condensation chamber 16 until a predetermined pressure is reached, and condensed frost having a desired thickness is formed on the inner surface of the condensation chamber.

  a. The actual gas type and moisture added to the condensing chamber 16 may be modified as appropriate by the user's choice within the knowledge of those skilled in the art to include sufficient moisture to generate condensed frost. Good. In the illustrated example, the gas and moisture filled in the condensation chamber 16 may be nitrogen or argon containing a sufficient amount of moisture.

  b. For example, nozzles, heaters and steam (not shown) may be used as the moisture source. Moisture may also be added to the condensation chamber 16 under vacuum. Subsequently, the vacuum is released in the condensation chamber 16 to generate a pressure difference with the generation chamber 13. As an illustrative example, moisture may be added to the condensation chamber 16 under high vacuum (eg, 1000 mT). Subsequently, the pressure may be gradually increased in the condensation chamber 16 until it becomes higher than the pressure in the generation chamber 13.

  c. Alternatively, moisture may be added to the condensation chamber when it is at atmospheric pressure or under a predetermined other pressure that is higher than the pressure in the production chamber (eg, 50 Torr to 300 Torr).

  8). The filling valve 24 of the condensation chamber 16 is closed.

  9. The ventilation valve 27 is opened to increase the pressure in the condensation chamber 16.

  10. Open the shutoff valve 20 between the generation chamber 13 (low pressure state) and the condensation chamber 16 (higher pressure state with condensed frost on the inner surface).

  a. Due to the rapid change in pressure, a strong turbulent gas flow is generated in the condensation chamber. The turbulent flow removes the frost that has been gently condensed on the inner surface of the condensation chamber and breaks the frost into relatively large ice crystals. The ice crystals mix with the gas stream and enter the production chamber to increase the effectiveness of the nucleation process in the production chamber. Ice crystals are rapidly injected into the production chamber 13 and distributed uniformly throughout the chamber and in all vials. Ice crystals serve as nucleation sites for themselves to grow in supercooled solutions. By making the ice crystals uniformly distributed, nucleation occurs in a short time in all the vials. The nucleation process for all vials begins at the top and descends and is completed within a few seconds.

  b. Also, after adding moisture to the condensation chamber under vacuum, the pressure in the production chamber and the pressure in the condensation chamber are equalized at a low pressure (eg, 50 Torr to 300 Torr), and then the relief valve or ventilation valve 27 in the condenser is turned on. It is also possible to open, increase the pressure in the condensation chamber 16 and inject ice crystals into the production chamber 13.

  FIG. 2 illustrates a miniature condenser 100 connected to a freeze dryer 102 having an internal condenser 104. The internal condenser 104 is not configured to generate condensed frost therein and requires additional seed chambers and associated hardware to be added. The lyophilizer 102 includes a production chamber 106 having a shelf 108 therein for carrying the product to be lyophilized.

  The compact condenser 100 includes a nucleation seeding generation chamber 110 that includes a surface 112 defining a cooling surface or frost condensation surface. The cooling surface 112 may be a coil, plate, wall, or any suitable shape so as to increase the area where frost is condensed within the nucleation seeding generation chamber 110 of the small condenser 100. The moisture injection nozzle 114 extends into the nucleation seeding generation chamber 110. Further, the moisture injection nozzle 114 includes a moisture injection valve or filling valve 116. A ventilation gas supply line 118 with a filter 120 is connected to the nucleation seeding generation chamber 110 by a vacuum release valve or ventilation valve 122. The nucleation seeding generation chamber 110 of the small condenser 100 is connected to the lyophilizer 102 via a nucleation valve 124.

  In operation, gas and moisture flow into the nucleation seeding generation chamber 110 generates condensed frost on concentric coils, plates, walls, or other surfaces 112. Since the pressure in the small condenser 100 is higher than the pressure in the freeze dryer 102, when the nucleation valve 124 and the ventilation valve 122 are opened, a strong turbulent flow of gas occurs in the nucleation seeding generation chamber 110. The frost that has been gently condensed on the inner surface of the coil, plate, wall or other surface 112 in the chamber 110 can be removed and the frost broken into ice crystals. The ice crystals mix with the gas stream and enter the generation chamber 106 to increase the effectiveness of the nucleation process in the generation chamber.

  FIG. 3 illustrates a small condenser 200 connected to a freeze dryer 202 having an external condenser 204. The configuration and operation of the small condenser 200 are the same as those of the small condenser 100 shown in FIG.

  This nucleation method is unique in that it combines the controllable pre-formation of condensed frost with the method of distributing ice crystals by abrupt pressure differences. This results in rapid nucleation due to large ice crystals that take only a few seconds, not minutes, regardless of the size of the system in which the method is used. This method provides the user with precise control of nucleation time and temperature and has the following advantages:

  1. The pre-formation of condensed frost in the external condensation chamber can be controlled, and the formation of ice crystals can be easily controlled.

  2. The pressure differential ratio can also be controlled to optimize the uniform distribution of ice crystals within a few seconds between all vials.

  3. Prior to actual nucleation, there is no local or batch temperature change of the product so that nucleation can be accurately controlled.

  4). The generation chamber is maintained at a negative pressure even after the introduction of ice crystals. There is no risk of positive pressure.

  5. This method can be used for any size lyophilizer having an external condenser and shut-off valve without any changes to the system. Other methods require extensive changes or costs.

  6). This method, when applied to a pharmaceutical manufacturing environment, can ensure a sealed, sterile operating mode.

  7). By applying the method of uniform nucleation to lyophilization, there is an advantage that a uniform crystal structure and an orderly crystal can be obtained over a wide range for every vial. Therefore, the initial drying process can be shortened.

  8). By forming condensed frost on the inner surface of the condensation chamber, a smaller condensation chamber with a densely condensed surface area could be used and added to any lyophilizer. Condensed frost requires a smaller volume than floating ice mist.

  9. Condensed frost is more stable, can be stored for a longer period of time, and can be used as needed compared to the gaseous state of floating ice mist (which must be generated just before the start of nucleation) .

  10. The frost-forming environment can be carefully controlled using high pressure in the condensation chamber (eg, 500 Torr), large volume and slow gas flow, and warmer condensation surface temperature (eg, below 0 ° C.). Thereby, it is possible to generate gently condensed frost that is crushed by the turbulent flow of the gas when the pressure is released and becomes ice crystals.

  11. Larger ice crystals resulting from condensed frost are denser than gaseous ice mist and frozen longer than gaseous ice mist when introduced into the production chamber to facilitate the nucleation process Stay in the state.

  12 Smaller condensers can be added to systems that do not have external condensers or that cannot produce frost condensed by existing condensers or that cannot be made sterile. Condensers can be added to existing ports of sufficient size, for example by changing the chamber door.

  From the above description, in the novel method of the present invention, after the condensed frost is generated by the condensation chamber outside the generation chamber of the freeze dryer, ice crystals are generated by the turbulent gas flow (from the condensation chamber). It is easily understood that it can be rapidly introduced into a low pressure). This method provides rapid and uniform product nucleation in different vials in the lyophilizer.

  The present invention has been described with respect to the most practical and preferred embodiments at present. However, the present invention is not limited to the disclosed embodiments, and conversely includes various modifications and equivalent substitutions within the scope of the technical idea included in the appended claims. It should be understood that it is intended.

Claims (12)

A method for controlling and enhancing product nucleation in a freeze dryer comprising:
Maintaining the product at a predetermined temperature and pressure in a chamber of the freeze dryer;
Producing a predetermined volume of condensed frost on the inner surface of the condensing chamber, separated from the generating chamber and connected to the generating chamber via a vapor port;
When the condensation chamber has a predetermined pressure higher than the pressure of the production chamber, the vapor port is opened to the production chamber, and the turbulent flow of gas that crushes the condensed frost into ice crystals. The ice crystals rapidly rush into the production chamber for uniform distribution within the production chamber and cause uniform and rapid nucleation of the product in different regions of the production chamber. Including the steps of :
A filling gas containing a predetermined humidity is introduced into the condensation chamber to generate the condensed frost,
Gas containing the moisture, or the condensation chamber is under atmospheric pressure, when in another pressure predetermined high than the pressure in the product chamber, Ru is introduced into the condensation chamber method.   A method for controlling and enhancing product nucleation in a freeze dryer comprising:
  Maintaining the product at a predetermined temperature and pressure in a chamber of the freeze dryer;
  Producing a predetermined volume of condensed frost on the inner surface of the condensing chamber, separated from the generating chamber and connected to the generating chamber via a vapor port;
  Open the ventilation valve of the condensation chamber to create a turbulent flow of gas that breaks the condensed frost into ice crystals that rapidly reach the production chamber for uniform distribution within the production chamber. And causing uniform and rapid nucleation of the product in different regions of the production chamber,
  A filling gas containing a predetermined humidity is introduced into the condensation chamber to generate the condensed frost,
  The filling gas is introduced into the condensation chamber when the condensation chamber is under vacuum,
  The vacuum is subsequently released in the condensation chamber and the pressure rises to a pressure higher than the pressure in the production chamber;
  The method wherein the vacuum is opened in the condensation chamber by opening the ventilation valve of the condensation chamber. 3. The steam port according to claim 1 or 2 , wherein the steam port has a shut-off valve between the generation chamber and the condensation chamber to open and close the flow of steam between the generation chamber and the condensation chamber. The method described. 4. The method of claim 3 , wherein a vacuum pump is connected to the condensation chamber to selectively reduce the pressure in the production chamber and the condensation chamber when the shut-off valve is open. . When the vapor port is open to the production chamber,
The pressure in the generation chamber is about 50 Torr,
The method according to claim 1 or 2 , wherein the pressure in the condensation chamber is about atmospheric pressure. When the vapor port is open to the production chamber,
The temperature of the product is about -5.0 ° C,
The method of claim 5 , wherein the temperature of the condensation chamber is less than 0 ° C. The condensation chamber has a filling valve,
The method according to claim 1 or 2 , wherein the filling valve is opened to introduce the moisture-containing filling gas into the condensation chamber and form the condensed frost. The method according to claim 1 or 2 , wherein the filling gas is a filtered ambient atmosphere, and moisture is contained in an amount of about 50 to 80% by volume. The method of claim 1 or 2 , wherein the fill gas is humidified nitrogen or argon. Above the inner surface of the condensation chamber, a plurality of, inner coil is defined by the internal plate or the inner walls, the method according to claim 1 or 2.   The method of claim 10, wherein the inner wall is coil-shaped to maximize the size of the inner surface. The method of claim 1 , wherein the pressure in the production chamber is less than atmospheric pressure.

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