System for scale-down the processes of freezing and thawing aqueous solutions of thermo-sensitive pharmaceuticals

Abstract

This disclosure relates to scale-down systems for freezing and thawing aqueous liquid mixtures of thermo sensitive substances. In at least one aspect, the system can comprise a first container that has a head-space and a liquid-space, with a substantially constant average transversal cross-section area in the liquid-space that does not change substantially with height. The first container holds a volume of liquid for a height of liquid, has a lateral active heat transfer area having an insulated lateral area ALIM, and has an equivalent radius sized to reproduce the equivalent radius of a second container. The first container further has a lateral heat transfer area in contact with the liquid-space. The first container is smaller than the second container, and the insulated lateral area is equal to or greater than the lateral active heat transfer area.

1 . A scale-down system for freezing and thawing aqueous liquid mixtures of thermo sensitive substances, the system comprising:
 a holder for holding a first container and   an insulator;   wherein the holder is outwardly surrounded by the insulator such that the insulator insulates at least 50% of holder and such that heat transfer between the first container and a second container is equivalent.   
     
     
         2 . The system according to  claim 1 , wherein the insulator comprises a deformable layer arranged for contacting the first container. 
     
     
         3 . The system according to  claim 2 , wherein the deformable layer is made of a resilient material having low thermal conductivity selected from the group consisting of: extruded polystyrene foam, polyurethane foam, and acrylonitrile butadiene rubber. 
     
     
         4 . The system according to  claim 1 , wherein the insulator comprises a frame arranged to press the first container against the deformable layer such that thermal insulation is maximized. 
     
     
         5 . (canceled) 
     
     
         6 . The system according to  claim 1 , wherein the insulator has a cavity arranged to be filled with either a thermal insulation material or a phase change material. 
     
     
         7 . The system according to  claim 6 , wherein the phase change material is selected from the group consisting of: a mixture of water and ethylene glycol, a mixture of water and sodium chloride, and a mixture water and ethanol, provided that the phase change material so selected has the same osmolality of an aqueous liquid mixtures of thermo sensitive substance. 
     
     
         8 . The system according to  claim 6 , wherein the phase change material further comprises a nucleating agent wherein the nucleating agent is either silver iodide or lead iodide. 
     
     
         9 . (canceled) 
     
     
         10 . The system according to  claim 1 , further comprising a second insulator for insulating a head-space region of the first container, wherein the second insulator has a layer of a phase change material such that thermal insulation is maximized. 
     
     
         11 . (canceled) 
     
     
         12 . The system according to  claim 1 , further comprising a first removable heat exchanger having fins and a second insulation layer attached to a metallic support. 
     
     
         13 . The system according to  claim 12 , wherein the second insulation layer has a thickness configured for obtaining an overall heat transfer coefficient between 1-100 W m −2  K −1  for natural air convection and between 10-100 W m −2  K −1  for forced air convention. 
     
     
         14 . The system according to  claim 12 , wherein the second insulation layer is made of a plastic selected from the group consisting of: poly-ethylene, polypropylene, polycarbonate, and polylactic acid, or the plastic is made of an elastomer selected from the group consisting of: natural rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber and nitrile rubber. 
     
     
         15 . (canceled) 
     
     
         16 . The system according to  claim 12 , wherein the fins and the metallic support are made of a material with a thermal conductivity higher than 2 W m −1  K −1 . 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The system according to  claim 1 , further comprising a metallic block with an internal flow of a temperature-controlled fluid or a thermoelectric element whose temperature is controlled by electric current. 
     
     
         20 . (canceled) 
     
     
         21 . A scale-down system for freezing and thawing aqueous liquid mixtures of thermo sensitive substances comprising a first container, wherein the first container:
 has a head-space and a liquid-space, with a substantially constant average transversal cross-section area (ATM) in the liquid-space that does not change substantially with height;   holds a volume of liquid (ATM) for a height of liquid (HM);   has a lateral active heat transfer area (ALM), having an insulated lateral area (ALIM);   has an equivalent radius (RM) defined as 2 ATM/(ALM/HM), sized to reproduce the equivalent radius of a second container holding a volume of liquid (VL) at a height of liquid (HL), with a transversal cross-section area (ATL) that does not change substantially with height;   has a lateral heat transfer area (ALL) in contact with the liquid-space and an equivalent radius (RL) defined as 2ATL/(ALL/HL);   wherein the first container is smaller than the second container;   
       said scale-down system having an ALIM that is equal or greater than the ALM. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The scale-down system according to  claim 21 , wherein HM is approximately equal to HL and RM is approximately equal to RL. 
     
     
         25 . The scale-down system according to  claim 21 , wherein the material of the walls of the first container is the same of the walls of the second container and wherein the ratio of average wall thickness between the first container and second container is in the range between 0.5 and 1.5. 
     
     
         26 . The scale-down system according to  claim 21 , wherein the bottom surface of the scale-down container and of the second container are insulated. 
     
     
         27 . The scale-down system according to  claim 21 , wherein the surface around the head-space region is insulated both in the scale-down container and in the large container. 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . The scale-down system according to  claim 21 , wherein the average overall heat transfer coefficient of the insulation layers is lower than 5 J/(m 2 ·s·K). 
     
     
         32 . The scale-down system according to  claim 21 , wherein a small low-conductivity bar with a diameter less than 5 mm and with a thermal conductivity less than 0.5 W m −1  K −1  is inserted inside the container and attached to the wall of the container in the head-space or opening regions and ends in the region furthest away from the thermal active walls.