GB1587409A

GB1587409A - Freeze drying

Info

Publication number: GB1587409A
Application number: GB4115876A
Authority: GB
Original assignee: BOC Ltd Australia
Current assignee: BOC Ltd Australia
Priority date: 1976-10-04
Filing date: 1976-10-04
Publication date: 1981-04-01
Also published as: DE2743993A1; IT1088209B

Description

(54) FREEZE DRYING (71) We, BOC LIMITED, trading as EDWARDS HIGH VACUUM INTERNATIONAL, of Manor Royal, Crawley, Sussex, an English company, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to freeze drying at reduced pressure, commonly known as vacuum freeze drying, by which is meant a process in which a material containing water is dried by first freezing the material and then separating from it the water originally present in it to leave dry material.

The drying process can be regarded as having two phases. The first phase is that of subliming at reduced pressure the ice formed from the free water in the original material.

The second is that of removing by desorption the moisture retained by various mechanisms in the otherwise-dry material. The sublimation and desorption phases may overlap during a freeze-drying process. The present invention is applicable to the desorption phase.

In such a process, the drying is effected by applying heat, and by extracting air, water vapour and other gases evolved from the material during the drying process. These two processes, i.e. heating and extracting, tend to work in opposite directions, in that the better are the conditions for extracting air and water vapour, the less efficiently can heat be transferred to the frozen part of the material, because one important heat-transmission path is through the molecules of the gases and vapours in the interstices of the dried material positioned above the air/ice interface. Conversely, the less favourable are the conditions for extracting gas or vapour, the greater is the amount of heat that can be transferred to the material and ice without causing the ice to melt.When one or other process is predominant, the freeze-drying process takes place at a rate which is less than maximum, given the nature of the material and its pre-treatment.

The present invention aims at providing freeze-drying apparatus in which the rate of drying is kept automatically at or near its maximum while keeping the material below its eutectic point.

Accordingly the present invention provides a freeze dryer, including a chamber adapted to be coupled to a vacuum pump or other means for extracting gas from the chamber; means for trapping water vapour drawn off with the gas; means for supplying heating energy to shelves or other surfaces in the chamber to heat frozen material in containers on the shelves; means responsive to the temperature of the still-frozen material being freeze-dried to adjust the rate of supply of energy to prevent the frozen material froni being heated above its eutectic point; means for measuring the rate at which the frozen material is being dried, and means for keeping this rate at or near its maximum consistent with the material being freeze dried remaining frozen and near its point of incipient melting.

In a conventional freeze drier for pharmaceutical or similar substances, the frozen material to be freeze-dried is, for example, placed in vials on shelves in a chamber of which the interior is able to be connected through a condenser to the inlet of a vacuum pump or like means for extracting both air and water vapour from the chamber. The shelves are usually spaced-apart vertically and provided with electrically-energised heaters.

Because of the different heat-transmission processes and paths which are operative during the freeze-drying process, there is an optimum balance to be struck between the rates of heat supply and vapour extraction.

(Because heat is conducted more efficiently through water vapour than through dry air, emphasis will be placed in this specification on the presence or absence of water vapour, when discussing the supply of heat to the frozen material. However, this is only for convenience, as both air and any desorbed or previously-occluded gas are also removed from the chamber during the freeze-drying process. It is therefore to be understood that the term 'vapour' includes any gaseous fluid).

If the extraction of vapour from the chamber is reduced or stopped, then heat is able to be supplied more efficiently to the dry solids/ice interface from the undersurface of the heated shelf positioned above the vial, because of the presence of vapour in the pores of the vapour-permeable dried material left behind as the interface moves through the frozen material during the freeze-drying process. In addition, the excess vapour in the chamber prevents heat from being extracted from the frozen material. These combine to cause the temperature of the frozen material to rise. If other measures were not taken, this would result in the frozen material having its temperature raised to above its eutectic-point, so that it would melt and the drying would proceed from the liquid phase, with possible consequent damage to the material.

It is usual in a freeze-drying process to adjust the rate of supply of heat as the process proceeds so as to avoid melting the frozen material and possible overheating of the material which has already been dried. Thus the maximum achievable rate of sublimation gradually decreases. The limit is reached when all the ice has sublimed and heat is required only to desorb residual water from the icefree material.

The rate of freeze-drying can be measured by various alternative methods all lying within the scope of the present invention.

One method is by measuring the rate at which vapour is evolved from the chamber. A second is to measure the rate of change of weight of the material being freeze dried. A third, and preferred, method is to assume that the rate of drying is proportional to the rate at which heat is supplied to the shelves supporting the material. A fourth is to measure the rate of movement of the dry solids/ice interface through the material as the ice sublimes.

The present invention will now be described by way of example with reference to the accompanying drawing, which is a diagrammatic view of one form of freeze drier of the present invention.

In the drawing the freeze drier is shown as having a chamber 2 having in it four shelves 4 each provided with an electrically-energised heater 6. Each shelf 4, except for the top one, supports several vials 8 containing frozen material to be freeze-dried. The vials have stoppers 10 loosely inserted in their mouths so that the vapour evolved from the material during the freeze-drying process is able to pass out of the interior of the vial into the chamber 2, from which it is extracted through an exhaust conduit 12 connected through a valve 14 and condenser 16 to a vacuum pump 18 exhausting to the atmosphere.

When the contents of all the vials have been dried, then the stoppers 10 are pushed fully home (by means of which are not shown in the drawing and which do not form part of the subject-matter of this invention) to prevent the ingress of moisture from the atmosphere before the vials have to be opened in order to provide access to their contents.

In the interior of chamber 2 is at least one thermocoupole or other probe 20 positioned within a vial so as to measure the highest temperature of the frozen material during the freeze-drying process. This temperature is usually at a maximum at the plane of contact of the frozen material with the base of the vial.

The thermocouple is connected to a control device 22 which is arranged so that when the temperature of the frozen material is approaching the eutectic point of the solution or suspension being freeze-dried, i.e. is nearing the point of incipient melting, the supply of heat is reduced or stopped to ensure that the material remains below the eutectic point, and hence remains frozen.

The control device 22 is fed from a source 28 of alternating voltage. It supplies the heating energy to the shelves 4 at a rate measured by a wattmeter 30. The wattmeter supplies a signal indicative of its instantaneous reading to a differentiator 24 connected to a valve controller 26 supplying one input to an AND gate 34. A clock 36 supplies a second input to gate 34 so that the output from controller 26 passes to a motor 32 controlling the position of valve 14 at times chosen by the clock 36, which is presettable accordingly.

As can be realised from the above, there are two methods by which the rate of supply of heat to the frozen material can be altered.

One is by altering the efficiency of vapour extraction from chamber 2, and therefore changing the efficiency of the heat-transmission path through the dried material. The second is by adjusting the rate of supply of electrical energy to heaters 6. In the present invention, these two controls are operated concurrently.

Because the wattmeter 30 supplies a signal which is a measure of the rate at which heat is being supplied to the freeze drier, the output signal from differentiator 24 is a measure of the rate at which the rate of supply is changing. Thus if the electrical energy is being supplied at a rate other than maximum, the output signal from differentiator 24 will be other than zero. The differentiator is designed so as to give a positive output signal when the rate of change of heating is positive, i.e. is less than its maximum, and is negative when the rate of change of heating is negative, i.e. is greater than the maximum.

The device 26 is intended to introduce a deliberate perturbation in the freeze-drying process. One such perturbation is effected by altering the position of the valve 14, so that the rate of extraction of gas and vapour, i.e.

the pressure in the chamber 2, is altered in a predetermined direction depending on the polarity of the input signal to device 26.

Another of several alternative perturbations would be to arrange to have gas bled into the chamber 2, or into the inlet of the vacuum pump, at an adjustable rate, leaving the valve 14 at a constant position, so that the pressure in the interior of the chamber is similarly altered in a desired direction. The device 26 is adapted to supply to motor 32 a signal causing the motor to move so as to open valve 14 by a desired amount at time intervals chosen by the setting of clock 36.

The present invention is based on the assumption that the rate of freeze-drying of the material in chamber 2 is at a maximum when the rate of supply of heating energy is also at a maximum. In the described embodiment of the invention, the rate of effective utilisation of heat by the frozen material is controlled as a function of the position of valve 14 throttling the flow of gas from chamber 2 to vacuum pump 18. Once steady conditions have been reached, it is necessary to decide if heat is being supplied at a maximum rate. To do this, the position of valve 14 is altered in the direction dictated by device 26.

For example, if the valve is opened further, the pressure in the interior of chamber 2 reduces. If the previous pressure had been too high for the freeze-drying to be carried out at its maximum rate, i.e. too much heat was being transmitted to the dry solids/ice interface through the overlying dried material, and not enought heat was being used to sublimate the ice, then the effect of lowering the pressure is to reduce or stop this overheating. This causes the temperature measured by thermocouple 20 to reduce, which accordingly causes controller 22 to increase the rate at which heating energy is supplied to the freeze drier. This increase in the flow of electricity is detected by wattmeter 30 and this leads, as described above, to a positive signal from device 26.Because the freeze-drying process is a relatively slow operation, time has to be given for the process to settle down after a deliberate perturbation has been introduced.

Thus the clock 36 is preset to allow the signal from device 26 to pass to motor 32 every ten minutes, say. If a previous movement of valve 14 in one direction had led to an increase in the efficiency of the freeze-drying process, the resultant positive signal from device 26 (the next time the clock 36 generates a gating signal) causes the motor 32 to alter the valve again in the same direction as previously, and by an amount dictated effectively by device 26. This iterative process continues until a further opening of the valve 14 reduces the efficiency of the freeze-drying process, i.e. the resultant drop in pressure reduces the amount of heat reaching the dry solids/ice interface, and therefore the rate of sublimation reduces.This leads to a tendency in the temperature of the frozen material to rise which is detected by the thermocouple 20 and alters controller 22 so as to reduce the amount of electrical energy. This in turn gives rise to a negative signal from device 26. When the gate 34 is next enabled by clock 36, the direction of movement of motor 32 is reversed so as to close valve 14 by a chosen increment.

This process is again iterative and continues until the signal from device 26 changes polarity, indicating that the rate of supply of heat to the freeze drier has dropped below its maximum. A reversing switch may be used to change the polarity of the signal from the differentiator as the point of maximum utilisation is approached from the opposite direction.

In order to start up the freeze-drying process, the valve 14 would normally be wide open, and the controller 22 would be in the position in which it supplies heat to the freeze drier at a maximum rate. The effect of this would be to cause the temperature of the frozen material to rise towards its point of incipient melting. As soon as it nears this point, the fact is detected by thermocouple 20 and the controller is operated so as to reduce the rate at which electricity is supplied. From previous experience, it is known approximately how long this should take from the start of the freeze-drying process. The clock 36 is preset so as to enable gate 34 at the end of this period, because the pressure-control mode of operation of the freeze drier would not function while heat was being supplied to the freeze drier at a maximum rate.As soon as the initial warm-up period is over, the device 26 supplies a positive signal causing motor 32 to close valve 14 by a chosen amount. Because the valve 14 was initially in its maximum-open position in order to start the freeze-drying process, the freeze-drier would probably not be operating at its optimum efficiency, so that closing valve 14 by a small amount would lead to an improvement in the freeze-drying rate, which is reflected in an increased demand for electrical energy.

The process thus continues as described above, with the valve 14 being incrementally closed at selected time intervals until it needs to start being opened similarly, because it has overshot the point of maximum efficiency.

Thus the present invention provides a dynamic control system in which the efficiency of a freeze-drying process is deliberately altered so as to make excursions on both sides of the point of maximum efficiency.

As these excursions are relatively limited, the freeze-drier on average is operated continuously at just below its maximum theoretical efficiency, despite variations in the load presented to the electrical energy supply as the freeze-drying process continues.

As an alternative to the step-wise adjustment of the valve 14, it is within the purview of the present invention to alter the position of valve continuously, as long as as the rate of adjustment is slower than the response time of the freeze-drier.

In the present invention, it is assumed that the vial fitted with the thermocouple 20 is typical of all the vials, and so the whole of the freeze-drying process is controlled by what is happening in that particular vial.

An alternative to the use of the thermocouple could be by using another form of temperature-responsive probe, such as a resistance thermometer, or a thermistor, or by measuring the electrical resistivity of the frozen material. Another approach is to infer the temperature of the dry solids/ice interface by isolating the chamber 2 from the condenser 16 and measuring the resultant rise of pressure in the chamber. In other words, one measures the saturated vapour pressure of the ice at the interface: the extent to which the pressure rises in a given time is a measure of the temperature of the interface.

It will thus be seen that the present invention provides means for maximising the utilisation of heat in a freeze drier, by controlling the pressure within the freeze drier, so as to keep the rate of freeze-drying at a maximum.

Also present in the freeze-drier, but omitted from the drawing for clarity, would be an override control adapted to detect the end of sublimation process and reduce the heat supply to that necessary to desorb the residual moisture from the material. This control could be operated manually or automatically.

WHAT WE ClAIM IS: 1. A freeze dryer, including a chamber adapted to be coupled to a vacuum pump or other means for extracting gas from the chamber; means for trapping evolved water vapour drawn off with the gas; means for supplying heating energy to shelves or other surfaces in the chamber to heat frozen material in containers on the shelves; means responsive to the temperature of the stillfrozen material being freeze-dried to adjust the rate of supply of energy to prevent the frozen material from being heated above its eutectic point; means for measuring the rate at which the frozen material is being dried, and means for keeping this rate at or near its maximum consistent with the material being freeze-dried remaining frozen and near its point of incipient melting.

2. A freeze dryer as claimed in claim 1, including means for measuring the rate of freeze drying by measuring the rate at which water vapour is evolved from the chamber.

3. A freeze dryer as claimed in claim 1, including means for measuring the rate of freeze drying by weighing the material being dried during the freeze drying process, and measuring the rate at which the weight changes.

4. A freeze dryer as claimed in claim 1, including means for measuring the rate at which the dry solids interface in the frozen material moves through the material as the ice sublimes.

5. A freeze dryer as claimed in claim 1, including means for monitoring the rate at which electrical heating energy is supplied to the freeze-dryer, and measuring changes in this rate.

6. A freeze dryer as claimed in any preceding claim, in which the temperatureresponsive means includes at least one probe positioned within a body of material being freeze-dried, the probe being connected to a controller in the path of electrical heating energy to the heaters of the freeze dryer.

7. A freeze dryer as claimed in claim 5, in which the rate-monitoring means includes a wattmeter in the electrical supply path, the wattmeter supplying a signal indicative of its instantaneous reading to a differentiator connected to a device for controlling the position of a valve in the vapour exhaust conduit from the freeze dryer chamber.

8. A freeze dryer as claimed in any preceding claim, including means for introducing a perturbation into the freeze-drying process at selected time intervals which are greater than the time constant of the freeze dryer.

9. A freeze dryer as claimed in claim 8, in which energisation of the pertubation means causes the pressure in the chamber to be altered incrementally.

10. A freeze dryer as claimed in claim 9, in which the pressure alteration is caused by altering the position of the exhaust valve by a chosen extent and in a direction indicated by the polarity of the signal from the differentiator.

11. A freeze dryer as claimed in claim 9, in which the pressure alteration is caused by permitting gas to be bleed into the interior of the chamber of the freeze dryer.

12. A freeze dryer substantially as described herein with reference to, and as shown, the accempanying drawing.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. As an alternative to the step-wise adjustment of the valve 14, it is within the purview of the present invention to alter the position of valve continuously, as long as as the rate of adjustment is slower than the response time of the freeze-drier. In the present invention, it is assumed that the vial fitted with the thermocouple 20 is typical of all the vials, and so the whole of the freeze-drying process is controlled by what is happening in that particular vial. An alternative to the use of the thermocouple could be by using another form of temperature-responsive probe, such as a resistance thermometer, or a thermistor, or by measuring the electrical resistivity of the frozen material. Another approach is to infer the temperature of the dry solids/ice interface by isolating the chamber 2 from the condenser 16 and measuring the resultant rise of pressure in the chamber. In other words, one measures the saturated vapour pressure of the ice at the interface: the extent to which the pressure rises in a given time is a measure of the temperature of the interface. It will thus be seen that the present invention provides means for maximising the utilisation of heat in a freeze drier, by controlling the pressure within the freeze drier, so as to keep the rate of freeze-drying at a maximum. Also present in the freeze-drier, but omitted from the drawing for clarity, would be an override control adapted to detect the end of sublimation process and reduce the heat supply to that necessary to desorb the residual moisture from the material. This control could be operated manually or automatically. WHAT WE ClAIM IS:

1. A freeze dryer, including a chamber adapted to be coupled to a vacuum pump or other means for extracting gas from the chamber; means for trapping evolved water vapour drawn off with the gas; means for supplying heating energy to shelves or other surfaces in the chamber to heat frozen material in containers on the shelves; means responsive to the temperature of the stillfrozen material being freeze-dried to adjust the rate of supply of energy to prevent the frozen material from being heated above its eutectic point; means for measuring the rate at which the frozen material is being dried, and means for keeping this rate at or near its maximum consistent with the material being freeze-dried remaining frozen and near its point of incipient melting.