PRINCE, Mark (53 Hereford Close, Rubery, Birmingham B45 0BQ, GB)
INGHAM, Andrew (10 Elia Street, Bradford Road, Keighley BD21 4BH, GB)
PRINCE, Mark (53 Hereford Close, Rubery, Birmingham B45 0BQ, GB)
| Claims : 1. A freeze drying apparatus, comprising: a) a vessel; and b) a collapsible element in an expanded configuration and capable of changing to a collapsed configuration; the freeze drying apparatus defining an internal volume able to receive and contain a liquefied product which is subsequently to be frozen; wherein the internal volume able to receive and contain the liquefied product is defined by the combination of the vessel and the collapsible element in its expanded configuration . 2. The freeze drying apparatus of claim 1 wherein the collapsible element is at least partially hollow. 3. The freeze drying apparatus of claim 2 wherein the collapsible element is a balloon element. 4. The freeze drying apparatus of any preceding claim wherein the collapsible element has a bistable structure and is capable of changing to the collapsed configuration by inward collapse of the collapsible element when subjected to an external force. 5. The freeze drying apparatus of any of claims 1 to 3 wherein the collapsible element is capable of changing to the collapsed configuration by electrical contraction of the collapsible element. 6. The freeze drying apparatus of any of claims 1 to 3 wherein the collapsible element is capable of changing to the collapsed configuration by inward collapse of the collapsible element when subjected to a reduction in air pressure. 7. The freeze drying apparatus of any preceding claim further comprising a one-way valve in communication with the collapsible element to prevent re-inflation of the collapsible element from the collapsed configuration to the expanded configuration. 8. The freeze drying apparatus of any of claims 1 to 3 wherein the collapsible element is capable of changing to the collapsed configuration by rupture of the collapsible element . 9. The freeze drying apparatus of any preceding claim wherein the collapsible element is separate from the vessel. 10. The freeze drying apparatus of any of claims 1 to 8 wherein the collapsible element is a part of the vessel. 11. The freeze drying apparatus of any preceding claim further comprising a closure for sealing the vessel. 12. The freeze drying apparatus of claim 11 wherein the collapsible element is connected to, or forms a part, of the closure . 13. The freeze drying apparatus of claim 12 wherein the closure comprises a stopper and the collapsible element comprises a balloon element depending from the stopper which is received within the internal volume of the freeze drying apparatus when the stopper is inserted, or partially inserted, into the vessel. 14. The freeze drying apparatus as claimed in any preceding claim, comprising a plurality of collapsible elements. 15. The freeze drying apparatus of any preceding claim wherein the vessel is a vial, ampoule or bag. 16. A freeze drying process comprising the steps of: a) at least partially filling a vessel with a product in liquid form; b) providing a collapsible element, wherein the collapsible element is in an expanded configuration and is at least partially submerged in the liquid product; c) freezing the liquid product to form a solid product at least partially surrounding the collapsible element such that an interface between the solid product and a surface of the collapsible element is created; d) collapsing the collapsible element into a collapsed configuration so as to expose a solid surface of the solid product which was previously in interface with the collapsible element; e) controlling the pressure and temperature in the vessel to cause sublimation of the solid product so as to effect freeze drying of the product. 17. The freeze drying process of claim 16 wherein the collapsible element is provided within, or as part of, the vessel prior to at least partially filling the vessel with the product in liquid form. 18. The freeze drying process of claim 16 wherein the collapsible element is inserted into the vessel after at least partially filling the vessel with the product in liquid form such that the collapsible element displaces a portion of the product in liquid form. 19. The freeze drying process of claim 17 or claim 18 wherein in step d) the collapsible element is collapsed by subjecting the collapsible element to an external force. 20. The freeze drying process of claim 19 wherein the external force is caused by expansion of the product in liquid form as it freezes within the vessel. 21. The freeze drying process of claim 17 or claim 18 wherein in step d) the collapsible element is collapsed by electrical contraction of the collapsible element. 22. The freeze drying process of claim 17 or claim 18 wherein in step d) the collapsible element is collapsed by reducing the pressure within the collapsible element. 23. The freeze drying process of claim 22 wherein the pressure within the collapsible element is reduced by exposing an interior of the collapsible element to at least a partial vacuum. 24. The freeze drying process of claim 17 or claim 18 wherein in step d) the collapsible element is collapsed by rupturing the collapsible element. 25. A freeze drying vessel, such as a vial or ampoule, for holding a liquefied product, the vessel at least in part defined by a wall, wherein an internal face of the wall comprises one or more interstices forming gas sublimation conduits . 26. A freeze drying vessel as claimed in claim 25 wherein the one or more interstices comprise an interstitial volume communicating with an interior volume of the vessel via an interstitial entrance opening, wherein the interstitial entrance opening has a critical dimension limited to prevent, by virtue of surface tension, entrance of said liquefied product into the interstitial volume. 27. A freeze drying vessel as claimed in claim 26 wherein the interstitial entrance opening has a width of up to and including 4.0 mm. 28. A freeze drying vessel as claimed in claim 27 wherein the interstitial entrance opening has a width of 0.2 to 2.0 mm. 29. A freeze drying vessel as claimed in claim 27 wherein the interstitial entrance opening has a width of greater than 0.2 μm. 30. A freeze drying vessel as claimed in any of claims 26 to 29 wherein the one or more interstices comprise a divergent cross-sectional shape, such that a width of the interstice increases from the interstitial entrance opening towards a base of the interstice. 31. A freeze drying vessel as claimed of claims 25 to 30 wherein the one or more interstices are defined by members which project inwardly from the internal face of the wall. 32. A freeze drying vessel as claimed in any of claims 25 to 30 wherein the one or more interstices are defined by grooves or other recessed structures formed in the internal face of the wall. 33. A freeze drying vessel as claimed in any of claims 25 to 32 wherein the interstices are formed integrally with the wall of the vessel. 34. A freeze drying vessel as claimed in any of claims 25 to 33 wherein the one or more interstices comprise tortuous gas sublimation channels. 35. A freeze drying vessel as claimed in any of claims 25 to 33 wherein the one or more interstices comprise elongate gas sublimation channels. 36. A freeze drying vessel as claimed in claim 35 wherein the elongate gas sublimation channels extend from at or near a bottom of the vessel towards an upper end of the vessel. 37. A freeze drying vessel as claimed in any of claims 25 to 36 wherein the vessel is formed from glass. N 38. A freeze drying process using the freeze drying vessel of any of claims 25 to 37, comprising the steps of: a) at least partially filling the vessel with a liquid product to be freeze dried, wherein ingress of the liquid product into the one or more gas sublimation conduits formed by the interstices is prevented by surface tension; b) cooling the vessel and liquid product to solidify the liquid product to form a solid product; c) controlling the pressure and temperature of the solid product to cause sublimation of vapour from the solid product; d) wherein at least a portion of the sublimating vapour from the solid product exits the vessel via the gas sublimation conduits formed by the one or more interstices. 39. A freeze drying vessel, such as a vial or ampoule, for holding a liquefied product, the vessel comprising an outer wall and an inner partition, wherein the inner partition separates a first volume for receiving in use the liquefied product from a second volume defining one or more gas sublimation conduits, wherein the partition comprises a plurality of apertures for transmission of vapour across said partition during a freeze drying process. 40. A freeze drying vessel as claimed in claim 39 wherein the apertures are in the form of holes, slits or similar openings . 41. A freeze drying vessel as claimed in claim 39 or claim 40 wherein the apertures each have a critical dimension of up to and including 4.0 mm. 42. A freeze drying vessel as claimed in claim 41 wherein the apertures each have a critical dimension of 0.2 to 2.0 mm. 43. A freeze drying vessel as claimed in claim 41 wherein the apertures each have a critical dimension of greater than 0.2 μm. 44. A freeze drying vessel as claimed in any of claims 39 to 43 wherein the gas sublimation conduit is an annular space defined between the partition and the outer wall of the vessel. 45. A freeze drying vessel as claimed in any of claims 39 to 44 wherein the gas sublimation conduit is a segment space defined between the partition and the outer wall of the vessel . 46. A freeze drying process using the freeze drying vessel of claims 39 to 45, comprising the steps of: a) at least partially filling the first volume of the vessel with a liquid product to be freeze dried, wherein ingress of the liquid product into the one or more gas sublimation conduits formed by the partition is prevented by surface tension at the apertures; b) cooling the vessel and liquid product to solidify the liquid product to form a solid product; c) controlling the pressure and temperature of the solid product to cause sublimation of vapour from the solid product; d) wherein at least a portion of the sublimating vapour from the solid product exits the vessel via the apertures and the one or more gas sublimation conduits. 47. A freeze drying process comprising the steps: a) partially filling a vessel with a first substance in liquid form; b) freezing the first substance to form a first solid in the vessel, wherein the first solid comprises a solid surface; c) inserting a second substance in liquid form into the vessel; d) freezing the second liquid to form a second solid, wherein the second solid comprises an interface with the solid surface of the first solid; e) controlling the pressure and temperature in the vessel to cause sublimation of the first solid so as to substantially entirely remove the first solid from the vessel so as to expose a solid surface of the second solid which was previously in interface with the solid surface of the first solid; f) controlling the pressure and temperature in the vessel to cause sublimation of the second solid so as to effect freeze drying of the second substance. 48. A freeze drying process as claimed in claim 47 wherein the first substance is aqueous. 49. A freeze drying process as claimed in claim 48 wherein the first substance is water. 50. A freeze drying process as claimed in any of claims 47 to 49 wherein the vessel is elongate and the vessel is tilted or laid on its side during step b) such that the solid surface of the first solid when formed extends at least partially along a longitudinal axis of the elongate vessel . 51. A freeze drying process as claimed in any of claims 47 to 50 wherein the vessel is upright during step d) . 52. A freeze drying process as claimed in any one of claims 47 to 51 wherein at step (b) the temperature of the first substance is reduced to -50 0C or colder. |
This invention relates to improvements in methods and apparatus for freeze drying. The process of freeze drying in order to dehydrate a product with an aqueous content is well known. The process generally comprises three stages. First the material is frozen to a temperature below its eutectic point. Secondly, the material undergoes primary drying whereby the pressure is lowered and sufficient heat is supplied to the material in order to cause the primary frozen water content to sublimate. Thirdly, the material undergoes secondary drying whereby the temperature is raised higher than in the primary drying phase and the pressure is lowered to less than that of the primary drying phase in order to cause evaporation of residual adsorbed water.
Freeze drying equipment is available to carry out the process of freeze drying. An example of such equipment is a shelf freeze-drier . The product to be freeze dried may be placed into individual containers, such as vials or ampoules, and the individual containers may be loaded into the freeze-drier . The door of the freeze-drier is sealed before the freeze-drier carries out the three stages of the freeze drying process. Once the three stages of the process are complete, the individual containers may be sealed inside the freeze-drier before the door of the freeze-drier is opened. This ensures that the freeze dried product does not come into contact with atmospheric water vapour once the freeze drying process is complete. Tray freeze drying most commonly used in the food industry uses a tray to retain a liquid volume on the shelf of the freeze drier. This liquid can then be processed through the same stages of freezing, primary drying and secondary drying, before typically being removed under atmospheric conditions.
Freeze drying equipment, including shelf and tray freeze-driers, have a high capital cost, and product loads which are limited in space, whilst being expensive to run. There is therefore a need to increase the volume of a product which can be dried in such equipment and also to increase the speed of the process. There is a tension between the desire to dry a larger volume of product and the desire to dry the product more rapidly.
The freeze drying process may be accelerated by increasing the surface area to volume ratio of the product to be freeze dried since the sublimating water vapour must cross the surface boundary formed between the solid surface of the frozen product and the controlled gas environment of the freeze-drier .
Many tray freeze driers are designed to accommodate a particular specification of individual container, such as a particular vial or ampoule.
In the past, one method for increasing the volume of material to be dried in a single batch has been to increase the volume of material to be dried in each individual container. Where the individual container is an (at least largely cylindrical) vial, increasing the volume of liquefied product to be dried will not alter its surface area and therefore the ratio of volume to surface area of the product is necessarily increased. In increasing the ratio of volume to surface area, the freeze drying process is slowed. Therefore, while there is an increase in the volume of freeze dried material, this is offset against an increase in the time taken to dry the material.
Surface area may be increased by using individual containers which are large in area but low in height. For example, a vial with a larger diameter may be used. However, increasing the diameter of the vial will mean that the number of vials which can be accommodated per shelf will be reduced. Therefore, while the speed of freeze drying will increase, the total volume of material which can be accommodated in the freeze-drier will reduce.
It is possible to replace vials with trays for maximum surface area. However, very few trays can be accommodated in the standard equipment. In addition, where trays are used the material would need subsequently to be transferred from the trays to individual sealable containers for onward storage. This is not always practicable.
There exists a need, therefore, to improve the speed of the freeze drying process whilst also maximising the volume of material which can be dried and also, preferably, increasing the efficiency of pre-existing freeze-drying machines .
Against this background there is provided by one aspect of the present invention a freeze drying apparatus, comprising: a) a vessel; and b) a collapsible element in an expanded configuration and capable of changing to a collapsed configuration; the freeze drying apparatus defining an internal volume able to receive and contain a liquefied product which is subsequently to be frozen; wherein the internal volume able to receive and contain the liquefied product is defined by the combination of the vessel and the collapsible element in its expanded configuration. Advantageously, the collapsible element provides a mechanism for increasing the surface area of a product that is frozen within the apparatus that is exposed to the surrounding atmosphere. This allows for faster subsequent freeze drying. Preferably, the collapsible element is at least partially hollow. In one example, the collapsible element is a balloon element.
A hollow, or partially hollow element such as a balloon element provides a structurally simple means of embodying the collapsible element. Since the element is at least partially hollow it is able to significantly reduce its volume when it moves into the collapsed configuration, thereby reliably detaching from the surface of the solid frozen product to be freeze dried. The collapsible element may have a bistable or similar structure which is capable of changing to the collapsed configuration by inward collapse of the collapsible element when subjected to an external force. For example, the walls of the collapsible element may have hinges or sections of reduced thickness or lines of weakness which are designed to allow folding inwardly of the walls under external pressure. Alternatively, one or more of the walls of the collapsible element may be arcuate and be configured to snap-through from convex to concave configurations under external pressure.
The external force to collapse the collapsible element can be derived from the expansion of the liquid product as it freezes and bears against the collapsible element. Alternatively, the force may come from the action of the subliming frozen product during the freeze drying process. In a further alternative, a mechanical trigger connected to the collapsible element can be utilised to directly pull on the element in order to collapse it.
The collapsible element may be capable of changing to the collapsed configuration by electrical contraction of the collapsible element. For example, the collapsible element may be formed from an electrically-responsive polymer such as a zone-drawn polypyrrole film as described in "Electrically induced contraction of zone-drawn polypyrrole films", H. Okuzaki, , T. Hattori, H. Morikage and Y. Yamada, Synthetic Metals, Volume 153, Issues 1-3, 21 September 2005, Pages 105-108 , Proceedings of the International Conference on Science and Technology of Synthetic Metals, or an electrically controlled contractile polymer as taught in US6,117,296 (Thomson). A collapsible element formed from such polymers will shrivel and shrink when a voltage is applied to them.
The collapsible element may be capable of changing to the collapsed configuration by inward collapse of the collapsible element when subjected to a reduction in air pressure. For example, reducing the internal pressure of the collapsible element by exposing an interior of the element to a low pressure atmosphere, such as a partial vacuum (of the type typically created in conventional freeze dryers) can be used to deflate the collapsible element akin to evacuating a balloon. Preferably the apparatus further comprises a one-way valve in communication with the collapsible element to prevent re-inflation of the collapsible element from the collapsed configuration to the expanded configuration. The one-way valve prevents re-entry of gas into the collapsible element once the freeze drying process has been completed. The collapsible element may be capable of changing to the collapsed configuration by rupture of the collapsible element. Rupturing the collapsible element can be achieved by piercing the element akin to puncturing a balloon. Alternatively, the structural strength of the collapsible element can be engineered such that the element bursts when subjected to either the force of the expanding product on freezing or the stresses of the partial vacuum drawn by the freeze dryer.
The collapsible element may be separate from the vessel. For example, the element may be a free body insertable into the volume of the vessel. The free body may be in the form of a closed, hollow body or in the form of an open-ended body.
The collapsible element may be a part of the vessel. For example, the collapsible element may form part of a wall of the vessel.
The apparatus may further comprise a closure for sealing the vessel.
Preferably the collapsible element is connected to, or forms a part, of the closure. Advantageously, this reduces the number of component parts of the apparatus and allows insertion of the collapsible element into the vessel in the same operation as partially stoppering the vessel.
In one specific example, the closure may comprise a stopper and the collapsible element comprises a balloon element depending from the stopper which is received within the internal volume of the freeze drying apparatus when the stopper is inserted, or partially inserted, into the vessel. The freeze drying apparatus may comprise a plurality of collapsible elements. For example, two of more collapsible elements can be provided.
The vessel may be a vial, ampoule or bag. The vessel may be rigid (such as a glass vial or ampoule) , semi-rigid (such as a plastic container) or flexible (such as a polymeric bag) .
The present invention also provides a freeze drying process comprising the steps of: a) at least partially filling a vessel with a product in liquid form; b) providing a collapsible element, wherein the collapsible element is in an expanded configuration and is at least partially submerged in the liquid product; c) freezing the liquid product to form a solid product at least partially surrounding the collapsible element such that an interface between the solid product and a surface of the collapsible element is created; d) collapsing the collapsible element into a collapsed configuration so as to expose a solid surface of the solid product which was previously in interface with the collapsible element; e) controlling the pressure and temperature in the vessel to cause sublimation of the solid product so as to effect freeze drying of the product.
The collapsible element may be provided within, or as part of, the vessel prior to at least partially filling the vessel with the product in liquid form.
Alternatively, the collapsible element may be inserted into the vessel after at least partially filling the vessel with the product in liquid form such that the collapsible element displaces a portion of the product in liquid form. In step d) the collapsible element may be collapsed by subjecting the collapsible element to an external force. For example, the external force may be caused by expansion of the product in liquid form as it freezes within the vessel. In step d) the collapsible element may be collapsed by electrical contraction of the collapsible element.
In step d) the collapsible element may be collapsed by reducing the pressure within the collapsible element. For example, the pressure within the collapsible element may be reduced by exposing an interior of the collapsible element to at least a partial vacuum.
In step d) the collapsible element may be collapsed by rupturing the collapsible element.
In another aspect, the present invention provides a freeze drying vessel, such as a vial or ampoule, for holding a liquefied product, the vessel at least in part defined by a wall, wherein an internal face of the wall comprises one or more interstices forming gas sublimation conduits. Advantageously, the interstices forming gas sublimation conduits effectively increase the surface area of the liquid to be dried, without significantly altering the volume.
Preferably, the one or more interstices comprise an interstitial volume communicating with an interior volume of the vessel via an interstitial entrance opening, wherein the interstitial entrance opening has a critical dimension limited to prevent, by virtue of surface tension, entrance of said liquefied product into the interstitial volume.
Advantageously, the interstitial entrance opening does not allow entrance of the liquefied product but does effectively increase the surface area. Preferably, the interstitial entrance opening has a width of up to and including 4.0 mm. More preferably, the interstitial entrance opening has a width of 0.2 to 2.0 mm. In one aspect, the interstitial entrance opening has a width of greater than 0.2 μm. As the skilled person will appreciate, the size of the entrance opening can be optimised for the particular solution that is to be dried. For example, solutions with high surface tensions can benefit from larger entrance openings. Preferably, the one or more interstices comprise a divergent cross-sectional shape, such that a width of the interstice increases from the interstitial entrance opening towards a base of the interstice.
Preferably, the one or more interstices are defined by members which project inwardly from the internal face of the wall .
Alternatively, the one or more interstices are defined by grooves or other recessed structures formed in the internal face of the wall. Preferably, the interstices are formed integrally with the wall of the vessel.
The one or more interstices may comprise tortuous gas sublimation channels or elongate gas sublimation channels. In other words the channels may be non-straight or straight. However, straight channels aligned with the longitudinal axis of the vessel provide for easier manufacture by means of processes such as moulding and physical or chemical etching.
More preferably, the elongate gas sublimation channels extend from at or near a bottom of the vessel towards an upper end of the vessel.
Preferably, the vessel is formed from glass. In another aspect the present invention provides a freeze drying process using a freeze drying vessel as described above, comprising the steps of: a) at least partially filling the vessel with a liquid product to be freeze dried, wherein ingress of the liquid product into the one or more gas sublimation conduits formed by the interstices is prevented by surface tension; b) cooling the vessel and liquid product to solidify the liquid product to form a solid product; vc) controlling the pressure and temperature of the solid product to cause sublimation of vapour from the solid , product; d) wherein at least a portion of the sublimating vapour from the solid product exits the vessel via the gas sublimation conduits formed by the one or more interstices.
The liquid product may be an aqueous product or be a solution including an organic solvent such as tertiary butanol .
In another aspect the present invention also provides a freeze drying vessel, such as a vial or ampoule, for holding a liquefied product, the vessel comprising an outer wall and an inner partition, wherein the inner partition separates a first volume for receiving in use the liquefied product from a second volume defining one or more gas sublimation conduits, wherein the partition comprises a plurality of apertures for transmission of vapour across said partition during a freeze drying process. Preferably the apertures are in the form of holes, slits or similar openings. Preferably the apertures each have a critical dimension of up to and including 4.0 mm. More preferably, the apertures each have a critical dimension of 0.2 to 2.0 mm. In one aspect, the apertures each have a critical dimension of greater than 0.2 μm.
The gas sublimation conduit may be an annular space defined between the partition and the outer wall of the vessel. Alternatively, the gas sublimation conduit may be a segment space defined between the partition and the outer wall of the vessel.
In another aspect the present invention provides a freeze drying process using the freeze drying vessel described above, comprising the steps of: a) at least partially filling the first volume of the vessel with a liquid product to be freeze dried, wherein ingress of the liquid product into the one or more gas sublimation conduits formed by the partition is prevented by surface tension at the apertures; b) cooling the vessel and liquid product to solidify the liquid product to form a solid product; c) controlling the pressure and temperature of the solid product to cause sublimation of vapour from the solid product; d) wherein at least a portion of the sublimating vapour from the solid product exits the vessel via the apertures and the one or more gas sublimation conduits.
The present invention further provides a freeze drying process comprising the steps: a) partially filling a vessel with a first substance in liquid form; b) freezing the first substance to form a first solid in the vessel, wherein the first solid comprises a solid surface; c) inserting a second substance in liquid form into the vessel; d) freezing the second liquid to form a second solid, wherein the second solid comprises an interface with the solid surface of the first solid; e) controlling the pressure and temperature in the vessel to cause sublimation of the first solid so as to substantially entirely remove the first solid from the vessel so as to expose a solid surface of the second solid which was previously in interface with the solid surface of the first solid; f) controlling the pressure and temperature in the vessel to cause sublimation of the second solid so as to effect freeze drying of the second substance.
Preferably, the first substance is aqueous. More preferably, the first substance is water. Preferably, the vessel is elongate and the vessel is tilted or laid on its side during step b) such that the solid surface of the first solid when formed extends at least partially along a longitudinal axis of the elongate vessel . Preferably, the vessel is upright during step d) .
Preferably, at step (b) , the temperature of the first substance is reduced to -50 0 C or colder.
The aspects of the present invention are not limited to any specific field of product to be freeze-dried. Indeed any solution, emulsion or colloid that can be freeze dried will benefit from the inventive apparatus and processes set out above. However, the invention is particularly appropriate for the freeze drying of aqueous pharmaceutical compositions such as for use in preparing vaccines, and for foodstuffs.
Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:
Figure 1 is a cross-sectional view of a vial and closure according to one aspect of the present invention;
Figure 2a is a cross-sectional view of a vial and closure according to another aspect of the present invention;
Figure 2b is a side elevation view of the closure of Figure 2a;
Figures 3a to 3d illustrate the method steps of a process of the present invention making use of the vial and closure of Figure 1;
Figure 4 is a perspective view of a vial and closure according to another aspect of the present invention with a part of the vial omitted for clarity;
Figure 5 is a perspective view of a vial and closure and a container and closure according to another aspect of the present invention with a part of the respective vial and container omitted for clarity;
Figures 6a to 6c illustrate the method steps of a process of the present invention making use of a vial according to another aspect of the present invention; Figure 7 is a cross-sectional view of a vial and closure according to another aspect of the present invention; Figure 8 is a cross-sectional view of a vial according to another aspect of the present invention;
Figure 9 is a graph showing rate of water loss during freeze drying using a process of the present invention compared to a standard process;
Figure 10 shows a prior art vial as commonly used to contain material during a freeze drying process;
Figure 11 shows a vial according to another aspect of the present invention; Figure 12 illustrates the method steps which make up a method according to another aspect of the present invention;
Figures 13a and 13b are graphs showing rate of water loss during freeze drying using a process of the present invention compared to a standard process; and Figure 14 shows a vial according to another aspect of the present invention.
Figure 10 shows a standard vial 1 known for use in freeze-drying processes which is described for comparative purposes. The vial 1 is bottle-shaped and comprises a cylindrical wall 10, a base 11, a neck 13 and an opening 14. The base 11 is perpendicular to the longitudinal axis of the cylindrical wall 10.
Figures 1, 2a and 2b show two similar embodiments of freeze drying apparatus according to the present invention. The apparatus comprises a vial 1 and a stopper 100. The vial 1 is conventional and comprises a cylindrical wall 10, a base 11, a neck 13 and an opening 14. The stopper 100 comprises an enlarged upper end 101 and a narrower plug 102 that depends from an underside of the upper end 101. The plug 102 has a part-circular form sized to fit in and seal with the opening 14 of the vial 1 and is provided with a slot 103 formed at one point on the circumference as best shown in Figure 2b.
The apparatus further comprises a collapsible element in the form of balloon element 110 that depends from an underside of the stopper 100. The balloon element 110 comprises a skin 111 of generally cylindrical form enclosing an interior 112. The skin 111 is closed at its lower end but at its upper end is joined by a narrow elongate section 113 to the stopper 100. A 1.5mm bore 114 extends from the interior 112 of the balloon element up the elongate section 113 and through the stopper 100 and terminates at a one-way valve 105 provided on the upper external face of the stopper 100. The one-way valve 105 may be of any conventional type and may, in some cases, be a simple flap valve biased to be normally closed.
The upper face of the stopper 100 is also provided with a raised ring 104 which is used to help locate a syringe needle during use of the vial after freeze drying. The stopper 100 and balloon element 110 are preferably integrally formed.
The length of the balloon element can be varied. The version of Figure 1 is longer and extends substantially to the bottom of the vial 1 when the stopper 100 is only partially inserted. The version of Figure 2 is shorter such that the balloon element is clear of the vial bottom when the stopper 100 is fully inserted.
The thickness of the skin 111 can be varied in order to cause collapse at the specified pressure drop. Typically the wall thickness may be 0.75mm and the balloon element may have a diameter of 8 mm. Figures 3a to 3d illustrate use of the apparatus (using the apparatus of Figure 1 by way of example) .
The apparatus is shown in Figure 3a with the stopper 100 partially inserted into the vial 1 (as it might be provided post filling) . The stopper 100 (and integral balloon element) is removed from the vial 1 and a liquid product 120 is filled into the vial through the opening 14. The amount of liquid filled can vary. The stopper 100 is then partially inserted into the vial 1 with the balloon element 110 extending down into the vial 1 to be partially submerged by the liquid product 120 as shown in Figure 3b. It should be noted, that with the stopper partially inserted the slot 103 of the stopper 100 extends above the upper rim of the vial opening 14 allowing gas exchange between the interior of the vial 1 and the surrounding atmosphere.
The apparatus is then inserted into a freeze dryer and the freeze drier is used to carry out the standard three stage freeze drying process. In stage one, the temperature is reduced causing the liquid product 120 in the vial 1 to freeze around the balloon element 110. During stage two
(primary drying) a vacuum or partial vacuum is drawn in the freeze dryer to cause sublimation of the water content of the product 120. At the same time the reduction in air pressure causes the balloon element 110 to collapse as shown in Figure 3c. This is due to the fact that the interior 112 of the balloon element is in communication with the exterior of the apparatus via the bore 114 and one-way valve 105 so that gas is evacuated from within the balloon element 110. At the same time gas is subliming from the product 120 creating a pressure differential across the skin 111 of the balloon element 110. As a result the skin 111 of the balloon element 110 is drawn in, up and away from the frozen product 120 revealing a much larger surface area of the frozen product 120 for further sublimation including a surface 121 that was previously at the interface between the frozen product 120 and the skin 111. The primary drying can then continue at an advance rate shown schematically in Figure 3d by the subliming product 122.
There is also the advantage that, in the third phase (secondary drying) the increase in surface area accelerates the evaporation of adsorbed water which was not sublimated in the primary drying phase.
Once the drying process has completed the stopper 110 is fully inserted by pushing down on the upper end 101 to seal the vial 1. The one-way valve 105 prevents gas entry into the interior 112 and thereby prevents re-inflation. The shape, size and configuration of the collapsible element can be varied. For example, Figure 4 shows another embodiment in which the collapsible element is in the form of a C-shaped balloon element 130 joined to the one-way valve 105 of the stopper 100 by the elongate section 113. The more convoluted shape of the C-shape balloon element 130 when collapsed results in an increased surface area for the solid face 122 compared to a cylindrical balloon element. Use of such a modified apparatus is as described above with reference to Figure 3a to 3d. The collapsible element 110 need not be connected to, or formed as part of, the stopper 110. In the embodiment shown in Figure 5, the interior 112 of the balloon element 110 is connected to the outside of the vessel by means of the elongate section 113 which in this embodiment is in the form of a tube having an open end 115. The tube 113 is able to pass out of the slot 103 of the partially inserted stopper 100. Figure 5 also illustrates how the present invention may be utilised with vessels of different sizes. On the left is shown a vial 1 as described above. On the right is shown a larger bulk container 1' of a type which is more suited for freeze drying of products, such as foodstuffs, that are typically freeze dried in larger quantities. The container 1' may have more that one collapsible element 110 located inside if desired. In addition, the collapsible element (s) 110 can be used with an open container, such as an open tray system that is not partially stoppered during the freeze drying process.
Instead, the tube 113 passes out of the open top of the container. Use of such a modified apparatus is akin to that described above with reference to Figure 3a to 3d.
Figures 6a to 6c show a further embodiment of the present invention wherein the collapsible element 110 is formed as a section of the vial 1 itself, such as part of the wall 10. As shown the collapsible element 110 extends inwardly into the interior of the vial. The interior 112 of the collapsible element 110 communicates with the exterior of the vial 1 via a small aperture 116 in the wall 10.
Alternatively, the position of the aperture 116 could be in the base 11 or neck 13 of the vial 1.
Preferably the vial 1 and collapsible element 110 can be formed as a single piece from a material such as a polymer or plastics. The skin of the collapsible element 110 can be made thinner than the thickness of the wall 10 of the vial 1. Alternatively, the vial 1 can be made from a rigid material such as glass and the collapsible element can be made from a flexible material such as a rubber or a polymer and then be bonded or otherwise connected to an aperture in the wall 10. As shown in Figures 6b and 6c use of this version of the apparatus is very similar to that shown in Figures 3a to 3d. As before, reduction in the exterior air pressure causes the collapsible element 110 to collapse (with the interior 112 of the collapsible element 110 evacuating through the aperture 116) and the skin 111 to draw away from the frozen product 120 revealing an increased surface area for freeze drying in the form of surfaces 121.
The vessel of the present invention may be provided with a plurality of collapsible elements 110 to provide a greater increase in the available surface area of the frozen product. For example, in the embodiment of Figure 7 the vial 1 has two collapsible elements 110 of the type described above, both connected to separate one-way valves 105 in the stopper 100. Alternatively, both interiors 112 could be joined to a single outlet via one or two elongate sections 113.
As noted above, the collapsible element 110 of the present invention need not be connected to the stopper 100. In addition, it is not necessary for the collapsible element to include a portion that extends outside the vessel. As shown in the embodiment of Figure 8, the collapsible element
110 may comprise a simple balloon element formed from a skin
111 which is at least partially submerged in the liquid product in the vial 1 before it is frozen. In the figure, the collapsible element 110 is provided with an aperture 117 through which the interior 112 can be evacuated. However, the collapsible element 110 may be designed to collapse in ways other than evacuation of the interior 112. For example, the structure of the collapsible element 110 may be bistable or have a similar structure which is capable of changing to a collapsed configuration by inward collapse of the collapsible element 110 when subjected to an external force. For example, the walls 110 of the collapsible element may have hinges or sections of reduced thickness or lines of weakness which are designed to allow folding inwardly of the walls 110 under external pressure. Alternatively, one or more of the walls 110 of the collapsible element 100 may be arcuate and be configured to snap-through from convex to concave configurations under external pressure. The external force to collapse the collapsible element can be derived from the expansion of the liquid product as it freezes and bears against the collapsible element 110. Alternatively, the force may come from the action of the subliming frozen product 120 during the freeze drying process. In a further alternative, a mechanical trigger connected to the collapsible element can be utilised to directly pull on the element in order to collapse it. In a further alternative the external force applied to the collapsible element can be used to burst or rupture the skin 111, for example at a line or zone of weakness.
Example
In the following example, freeze drying using conventional vials without any collapsible element were compared to apparatus of the present invention which included a collapsible element:
20ml freeze drying vials (Scholl, UK) where obtained and equipped with standard one port freeze drying stoppers (West company, Germany) . Hydrophobic bags representative of the displacement potential of those in Figure 2a were manufactured in sealed units. For the control vials no bags were inserted (labelled ^CONTROL' in Figure 9) . For the vials according to the present invention a bag was placed inside each vial (labelled 'TEST' in Figure 9) . Two solutions were tested, 3%w/v Sucrose (labelled Λ S' in Figure 9) and 3%w/v Lactose (labelled Λ L' in Figure 9) . The vials were loaded and frozen to a temperature of - 40 0 C over 45 minutes. The material bags in the TEST vials were then mechanically burst before removal.
Freeze drying was then carried out on all vials at a constant shelf temperature below the collapse points of both formulations. As shown in the results of Figure 9, the vials of the present invention with the increased surface area (TEST L and TEST S) produced significantly increased rates of freeze drying. For example, the freeze drying of the sucrose vial with the collapsible element (TEST S) had completed by 63 hours whilst the prior art valve (CONTROL S) still contained nearly 30% water at the same time.
The vessels of the invention described in the above embodiments, such as vials, may be capped in the standard manner using the apparatus already available inside many freeze-driers .
The stopper 100 and collapsible element 110 are formed from any suitable material such as bromobutyl rubber, chlorobutyl rubber, a silicone or a plastics material having suitable plasticisers . The internal and/or external surfaces of the stopper 100 and collapsible element 110 may be coated with a substance to reduce sorption of the product. The internal surface of the collapsible element 110 may be coated with an adhesive agent such that on collapse of the element the skin 111 sticks to itself thereby resisting re- inflation of the collapsible element. The format and arrangement of the vents in the stopper may be varied as known in the art. See for example the teaching of US5,596,814 (Zingle et al) .
The size of the vessel, such as a vial or ampoule, may be freely varied depending on the nature and volume of the product to be freeze dried. For example, common vial sizes receive stoppers of DIN sizes of 13 to 32 mm.
Figure 11 shows a further embodiment of vial 1 according to another aspect of the present invention. As with the known vial of Figure 10 it comprises a cylindrical wall 10, a base 11, and an opening 14. (For ease of illustration, this vial 1 is shown without a constricted neck 13 section but can include such a neck where desired. ) The interior wall 10 of the vial 1 comprises a number of elongate protrusions 21-24 which are parallel to the axis of the cylindrical wall 10. The protrusions 21-24 are such as to define therebetween a plurality of channels 15 or interstices which run the full length of the wall 10. The channels 15 have a mouth opening 18 which is parallel to the longitudinal axis of the vial 1 and an end opening 19 which is perpendicular to the longitudinal axis of the vial.
The specific example of Figure 11 shows a number of alternative designs of elongate protrusion 21-24 which result in differing designs of resulting channel 15. Each vial 1 may have protrusions which are all of the same design or protrusions of mixed design within the same vial 1.
The protrusions 21 are largely triangular in cross- section (except that the side of the triangle which meets the wall 10 of the vial 1 has a slight curve in order to correspond with the curve of the wall 10) . The opposing faces of the two triangular-shaped protrusions 21 are parallel such that the channel formed between the two triangular-shaped protrusions 21 is substantially rectangular in cross-section.
The protrusions 22 are also largely triangular in cross-section (except that the side of the triangle which meets the wall 10 of the vial 1 has a slight curve in order to correspond with the curve of the wall 10). The opposing faces of the two triangular-shaped protrusions 22 diverge in an outwardly radial direction with respect to the vial 1 such that the channel 15 formed therebetween has a cross section which is substantially an isosceles trapezium.
The protrusions 23 have an external cross-sectional shape which is similar to that of the protrusions 22 but their internal cross-sectional shape is thinner to allow for a less restricted flow of gas in the channel region.
The protrusions 24 have a largely cylindrical cross- section. The cross section of the channel 15 is formed by the wall of the vial 1 and the internal facing surfaces of the adjacent cylindrical protrusions 24. Such a design of elongate protrusion is less intricate than some of the previous examples and is therefore more simple to manufacture. In Figure 11 the two cylindrical protrusions 24 are shown with different diameters. Of course, the protrusions 24 may have the same or different diameters. For any design of protrusion 21-24, the mouth opening
18 of the channel 15 is the location at which the channel 15 meets the main volume of the vial. The width of the channel mouth opening 18 is between 0.2 mm and 2.0 mm. This dimension is chosen in order to prevent, by virtue of surface tension, a liquid in the main volume 12 of the vial 1, from entering into the channels 15. In the example of Figure 11, the width is 0.50 mm. As the skilled person would readily appreciate, the exact design of the elongate protrusions and the resulting elongate channels is not limited to the examples provided herewith. Furthermore, the skilled person would appreciate that a vial in accordance with an embodiment of the present invention may comprises any number of elongate protrusions. In addition, the channels 15 may be formed as grooves in the wall 10 formed by a moulding or etching process or similar. The embodiment of the invention requires only that one or more channels are provided and that the width of the channel mouth opening 18 is such as to prevent, by virtue of surface tension, a liquid which is poured into the main volume 12 from entering the channel 15.
The channels 15 need not necessarily extend the full length of the vial. They need only to be tall enough so that the volume of liquid to be freeze-dried in the main volume 12 will not flow over the top of the channels (via the end openings 19) into the channels 15.
Moreover, the channel 15 need not be of uniform cross section throughout its length. It is critical only that the channel mouth opening 18 is such as to prevent, by virtue of surface tension of the liquid, the entrance of the liquid into the channel 15.
Viscosity of a liquid has an influence on its surface tension. Therefore, the exact dimensions of the channel mouth opening 18 may be chosen to maximise, for a particular liquid, the dimension (and so maximise the increase in surface area of the product) whilst minimising the risk that the liquid will break into the channel 15. In use, a liquid to be freeze dried is poured into the main volume 12 of the vial 1 through the opening 14. By virtue of the surface tension of the liquid and the width channel mouth opening 18, the liquid is prevented from passing into the elongate channels 15.
When inserted into a freeze-drier, the vial is loaded in a vertical orientation. The freeze drier is used to carry out the standard three stage freeze drying process. In stage one, the temperature is reduced in order to freeze the liquid in the main volume 12 of the vial 1. The major advantage of the vial of this embodiment of the present invention is that, in the second stage (the primary drying stage) , the surface area of the (now frozen) product which is exposed to the atmosphere in the freeze-drier is larger than for a conventional vial since, not only is the top surface of the frozen product exposed, but also those parts of the frozen product adjacent to the channel mouth openings 18 are exposed since the volume of the channels 15 is in gas communication with the open mouth 14 of the vial 1. This accelerates the sublimation of frozen water from the product to be freeze dried. There is also the advantage that, in the third phase (secondary drying) the increase in surface area accelerates the evaporation of adsorbed water which was not sublimated in the primary drying phase.
Finally, the vials may be capped in the standard manner using the apparatus already available inside many freeze- driers since the presence of the protrusions 21-24 and channels 15 will not require any alteration to the standard caps or the capping process.
While the specific example described above is a largely cylindrical vial, the skilled person will appreciate that the vial of this embodiment need not be largely cylindrical in cross section. It may have any cross section such as, for example, a largely square cross section. Furthermore, the vessel need not be a vial and may be an ampoule or another form of container.
The vial may be made from glass and may be formed by injection moulding. The protrusions may be formed by injection moulding or etching or similar.
A further embodiment of the present invention is shown in Figure 14. As with the known vial it comprises a cylindrical wall 10, a base 11, and an opening 14. (For ease of illustration, the vial 1 is shown without a constricted neck 13 section but can include such a neck where desired. )
In this embodiment the gas sublimation channel 15 is formed as an annular space 15 between the outer wall 10 of the vial 1 and an inner partition 40 in the form of a cylindrical tubular member inserted into the vial. The partition 40 separates a first volume 43 inside the partition from the second volume of the gas sublimation channel 15. The partition 40 comprises a plurality of apertures 41 in the form of small holes. An open top 42 of the partition 40 communicates with the mouth 14 of the vial. The critical dimension of the apertures 41 is sized to prevent, by virtue of surface tension, a liquid in the first volume 43 of from entering into the channels 15. Where the apertures 41 are holes the dimension may be, for example, 0.50 mm.
The partition 40 may be formed from a rigid or flexible material. Examples include metal, glass or plastic as well as textiles or membranes that exhibit vapour transmission abilities, for example, GoreTex (RTM) .
As the skilled person would readily appreciate, the exact design of the partition and the resulting channel or channels is not limited to the example provided herewith. For example, the partition could be flat and separate the vial cross-section into two segments forming respectively the first volume and the gas sublimation conduit. The apertures need not be circular holes but could be of other shapes such as slits.
A further embodiment of the present invention relates to a method of freeze drying using an industry standard vial, ampoule or similar container. The method steps are illustrated in Figure 12.
The method involves taking an industry standard vial 1 and inserting a volume of a first product in liquid form (for example water or an organic solvent such as tertiary butanol) . The volume of the first product is chosen to be such that when the vial 1 is placed on its side the first product will not be higher than the neck 13 of the vial 1 so it will not flow out of the opening 14 of the vial 1 (see Figure 12a) . The vial 1 is placed on its side in a cold environment (such as a freezer but not necessarily a freeze-drier) until the first product is frozen to provide a solid volume 30 of the product which extends along the length of the vial 1 and comprises a solid face 31. The vial 1 may then be placed in a vertical orientation and the first product, now frozen, will remain in position (Figure 12b) such that the solid face 31 will be vertical. In a subsequent stage of the process, the first product will provide a preferential sacrificial layer. Preferably, the temperature of the fist product is reduced to -50 0 C or colder. The product to be freeze dried (the second product) is cooled to a temperature just above its freezing temperature and then inserted into the remaining volume of the vial 1 (that is the volume not occupied by the first product 30) when the vial 1 is an upright position (Figure 12c) .
Since, at this point, the temperature of the first product 30 is preferably -50 0 C and the temperature of the second product 35 is, ideally, fractionally higher than its own freezing point (which, in the case of most products to be freeze dried is fractionally higher than 0 0 C) , any melting of the first product 30 as a consequence of coming into contact with the second product 35 is minimised.
The vial 1 may then be placed in a freeze drier as normal. During a first stage, the second product 35 is frozen due to the low temperature in the freeze drier to form a second solid 35.
During a second stage, the temperature and pressure within the freeze-drier is controlled in a known manner to cause sublimation of the water content (and/or organic solvent content) in the vial. The sacrificial layer 30
(comprising the first product) will sublime rapidly relative to the second product 35 since it is of a pure material such as water or an organic solvent. Once the sacrificial layer 30 has sublimed, this will leave a solid surface 36 of the second product 35 where the second product 35 was previously interfacing the solid face of 31 of the first product 30. Since the sacrificial layer 30 has now been removed, the solid face 36 is in gas communication with the opening 14 of the vial 1 and the atmosphere inside the freeze-drier (Figure 12d) . Thus, the surface area of the second product 35 comprises not only a plane which is perpendicular to the elongate axis of the vial 1 but also a plane which is parallel to the elongate axis of the vial 1.
Consequently, the surface area of the second product 35 is significantly increased. This increase in surface area of the second product 35 allows the water content in the second product 35 to sublimate more rapidly.
During a third stage, the conditions in the freeze- drier are altered to cause adsorbed water in the second product 35 to evaporate. Again, the increased surface area of the second product 35 allows this process to occur more rapidly.
Finally, the vial 1 may be sealed using known techniques within the freeze-drying apparatus without the need for any alteration to the apparatus.
Example
A first product to be freeze dried in the form of a sucrose (3%w/v) amylase (10U/ml) solution was used to investigate the rate of primary drying in both an ampoule and a vial design of container. A 3ml fill volume of the sucrose amylase was used. The volume of the ampoule was 5ml and the volume of the vial was 20ml.
In accordance with the embodiment of the invention described above, water was used as the second product to form the additional sacrificial layer of water. A volume of ImI of water was added to form the 'water wall' . The freeze drying process was stopped at successive time points during the primary drying phase to determine the extent of any benefit to primary drying rate by use of the water wall. The mass loss of water during sublimation was determined using a sartorius digital balance after freeze drying at fixed shelf temperature of -50 0 C (-80 0 C condenser 200mTorr) for defined periods of time. The results are shown in Figures 4a and 4b. Figure 13a shows the percentage of mass remaining after 39 hours and 56 minutes of primary drying. Figure 13b shows the percentage of mass remaining after 61 hours and 10 minutes of primary drying. As can be clearly seen use of the sacrificial second product wall to increase the surface area to volume ratio leads to significantly more efficient freeze drying. It is further expected that vials and ampoules having higher fill ratios (i.e. having a greater volume of first product compared to the 3 ml of product in the example above) will display an even greater benefit by using the current inventive process.