GB2120370A

GB2120370A - Freeze dryer apparatus

Info

Publication number: GB2120370A
Application number: GB08310036A
Authority: GB
Inventors: George Keith Emerson Gregory
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1982-05-11
Filing date: 1983-04-13
Publication date: 1983-11-30
Also published as: GB2120370B; GB8310036D0

Abstract

A freeze dryer apparatus includes supports (3) for supporting the products to be freeze dried. The supports are heated or cooled by circulating a heat exchange liquid within the supports. Two storage containers (5, 6) store the heat exchange liquid at two different temperatures and the liquid from either storage container can be circulated within the supports to enable the temperature of the supports to be changed rapidly. <IMAGE>

Description

SPECIFICATION Freeze dryer apparatus This invention relates to freeze dryer apparatus.

In a conventional freeze dryer apparatus the product to be freeze dried is either frozen outside the vacuum chamber and then placed in the vacuum chamber for further processing or in some instances frozen in the vacuum chamber itself. The vacuum chamber commonly contains supports such as shelves which support the products to be freeze dried and the supports are cooled at the beginning of each freeze drying cycle either to freeze the product prior to freeze-drying or to maintain the product in the frozen state. The pressure within the chamber is then reduced and heat is provided to the frozen product in order to sublime ice in the product into vapour. Heat is normally provided by heating the supports upon which the frozen product is supported. The water vapour sublimed from the frozen product is generally removed by condensation.The process of freeze drying is normally carried out as a batch process and the supports are cooled at the end of the cycle in preparation for commencement of the next cycle.

In freeze drying most products, such as biological materials, by a batch process the cycle time is relatively long, for example 24 hours, and thus the time taken for heating and cooling the supports is not a limiting factor in the length of the cycle. In the past the supports were cooled by, for example, circulating refrigerant within the supports (so that the supports act as an evaporator of the refrigeration system) or circulating cold liquid within the supports. When it was desired to heat the supports it was customary to employ a direct electrical heater or to heat up the circulating cold liquid (where this was also used to cool the supports). These methods cannot produce a rapid change of operating temperature of the supports unless uneconomic large heating and cooling capacities are used in the heating and refrigeration plants.In freeze drying certain compositions such as those exemplified below the cycle time can be considerably reduced, for example to 3 hours or less, by suitable choice of operating conditions. With such short cycle times the time taken to cool the supports at the end of the cycle can be a large percentage of the total cycle time if the conventional methods of heating and cooling the supports are used. This is an uneconomic use of the freeze drier and it is highly desirable to reduce the time taken to cool the supports at the end of each cycle so that the next cycle can be commenced as soon as possible.Also with such short cycle times it is desirable to heat the supports to the desired operating temperatures as rapidly as possible and this can take some time with conventional methods of heating especially if its is desired to heat the supports to a higher temperature than that used in conventional batch freeze drying procedures. We have now found that rapid change of temperature of the supports (and hence of products on the supports) can be attained by the freeze dryer apparatus of the present invention.

According to the present invention there is provided a freeze dryer apparatus comprising a chamber, a pump for reducing the pressure within the chamber, a condenser for condensing vapour produced during the freeze drying process, one or more supports within the chamber for supporting the products to be freeze dried, means for heating or cooling the supports by circulating heat exchange liquids within the supports, a first storage container for storing the heat exchange liquid at a first temperature, a second storage container for storing the heat exchange liquid at a second temperature, the second temperature being higher than the first, and valve means for circulating either the liquid from the first container or the liquid from the second container to the means for heating or cooling the supports.

The heat exchange liquid is common to both storage containers so that the liquid from either container may be easily circulated within the supports. This simplifies the construction of the supports and the accompanying pipework, beside allowing rapid change of temperature of the supports. The liquid is chosen to be suitable (with respect to, for example, freezing point, viscosity, toxicity and corrosivity) at both the first and second temperatures. The first temperature can be, for example, about -10 to -300C while the second temperature may be about 500 or higher, e.g. about 50 to 900C. We have found that by suitable choice of conditions it is possible to prepare freeze dried pharmaceutical dosage forms such as those described in our UK Patent No.

1,548,022 by a batch process within a cycle time of about 1 hour or less using a relatively high temperature for the support, e.g. up to about 900 C.

The temperature of the liquid in the first container may be maintained by refrigeration while the second container may be heated by, for example, an electrical heater or a steam coil or jacket.

Examples of heat exchange liquids include water containing ethylene glycol antifreeze, polymeric silicon fluids, trichlorethylene and mineral oil. The choice of heat exchange liquid will depend inter alia on the required first and second temperatures.

The heat exchange liquid may be circulated within the supports through channels between opposing surfaces of the supports.

The apparatus of the present invention is particulariy advantageous in freeze drying the compositions described in UK Patent Specification 1,548,022. Thus the present invention particularly provides a process for freeze drying a composition comprising a unit dosage of pharmaceutical substance and a solution of a pharmaceutically acceptable water-soluble or water dispersible carrier material in a solvent to produce a solid pharmaceutical dosage form comprising a network of the carrier material carrying a unit dosage of pharmaceutical substance which process comprises freeze drying the composition in an apparatus of the present invention.

A freeze dryer apparatus in accordance with the invention will now be described with reference to the figure in the accompanying drawings which represents a diagrammatical plan view of the apparatus.

As shown in the figure the apparatus comprises a chamber 1 having a door 2. Situated within the chamber are a series of horizontal stationary shelves arranged vertically above each other. One shelf 3 is shown. The pressure within the chamber 1 may be reduced by means of a vacuum pump (not shown). A cooled condenser (not shown) is also connected to the chamber to condense the water vapour produced in the freeze drying process.

Within the interior of the sheif 3 is a coiled pipe 4 (shown in dotted line). A reservoir 5 for heat exchange liquid is maintained at about 50 to 90"C. A similar reservoir 6 for the common heat exchange liquid is maintained at -10 to --300C.

The outlets of reservoirs 5 and 6 are connected by pipes 7 and 8 respectively to the inlet of the coiled pipe 4. Flow through the pipes 7 and 8 is regulated by means of valves 9 and 10 respectively and the liquid is pumped into the coiled pipe 4 by means of a circulation pump 11.

The outlet of the coiled pipe 4 is connected to the inlet of the reservoirs 5 and 6 by means of the pipes 12 and 13. Flow through the pipes 12 and 13 is controlled by valves 14 and 15.

When it is desired to cool the shelves 3, valves 10 and 1 5 are opened and valves 9 and 14 are closed. Cool liquid from reservoir 6 is then pumped by pump 11 through pipe 8 into the coiled pipe 4 and out through pipe 13. When it is desired to heat the shelves 3 valves 10 and 1 5 are closed and valves 9 and 1 3 are opened. Warm liquid from reservoir 5 is then pumped by pump 11 through pipe 7 into coiled pipe 4 and out through pipe 12.

The following Examples illustrate the preparation of freeze dried pharmaceutical dosage forms employing the apparatus of the present invention: EXAMPLE 1 Pharmaceutical Dosage Forms containing 1 5 mg Oxazepam Formulation: Oxazepam 1 5 mg Tween 80 BPC 0.25 mg Mannitol BP 1 5 mg 3% hydrolysed gelatin to 0.5 ml The 3% hydrolysed gelatin is prepared by suspending 30 g of powdered gelatin in 800 ml of cold distilled water in a 1 litre flask and autoclaving it at 121 OC for 60 minutes. When cool, the final volume is adjusted to 1 litre.

Oxazepam (30 g) is suspended in 3% hydrolysed gelatin solution containing dissolved mannitol (30 g) and Tween 80 (0.5 g) using ultrasonics for minutes and the suspension made up to 1 litre with 3% gelatin solution. 0.5 ml portions of the suspension are dosed, using an automatic filling machine, into pockets in polyvinyl chloride blister trays. Each of the pockets in the blister tray is of inverted truncated conical shape of 3.5 mm depth, a bottom diameter of 14.5 mm and a top diameter of 16 mm (i.e. the side walls make an angle with the vertical of about 100). The contents of the pockets are then frozen by passing the trays through a freeze tunnel into which liquid nitrogen is injected.

The blister trays containing the frozen compositions are then transferred to a freeze drier of the present invention in which the shelves are maintained at about -1 00C by circulating the heat eachange liquid from the cold reservoir. The pressure is adjusted to 1.5 mm Hg. The temperature of the shelves in the freeze drier is then raised to 60"C for 1 hour by circulating the heat exchange liquid from the warm reservoir.

After this time the temperature of the shelves are reduced by circulating the heat exchange liquid from the cold reservoir and the trays are removed from the freeze drier. A peelable aluminium foil is then sealed to the blister pack around the depressions containing the pharmaceutical dosage forms. The pharmaceutical dosage forms are of substantially uniform thickness and disintegrate rapidly, for example, in two seconds or less, when taken orally.

EXAMPLES 2 to 11 Following the procedure of Example 1, similar pharmaceutical dosage forms are prepared containing the following active ingredients: 2. Oxazepam 30 mg and 50 mg 3. Lorazepam 1,3,2.5and4mg 4. Temazepam 10 and 20 mg 5. Lormetazepam 1 mg 6. Frusemide 40 mg 7. Bendrofluazide 5 mg 8. Cyclopenthiazide 0.5 mg 9. Isosorbide dinitrate 2.5, 5 and 10 mg 10. Indomethacin 25 and 50 mg 11. Prochlorperazine maleate 50 mg

Claims

1. A freeze dryer apparatus comprising a chamber, a pump for reducing the pressure within the chamber, a condenser for condensing vapour produced during the freeze drying process, one or more supports within the chamber for supporting the products to be freeze dried, means for heating or cooling the supports by circulating a heat exchange liquid within the supports, a first storage container for storing the heat exchange liquid at a first temperature, a second storage container for storing the heat exchange liquid at a second temperature, the second temperature being higher than the first, and valve means for circulating either the liquid from the first container or the liquid from the second container to the means for heating or cooling the supports.

2. An apparatus as claimed in Claim 1 wherein the first temperature is about -10 to --300C.

3. An apparatus as claimed in Claim 1 or 2 wherein the second temperature is about 50"C.

4. An apparatus as claimed in Claim 1 or 2 wherein the second temperature is about 500 to 900C.

5. An apparatus as claimed in any one of Claims 1 to 3 wherein the heat exchange liquid is water containing an ethylene glycol antifreeze, a polymeric silicon fluid, trichlorethylene or mineral oil.

6. A process for freeze drying a composition comprising a unit dosage of pharmaceutical substance and a solution of a pharmaceutically acceptable water-soiuble or water dispersible carrier material in a solvent to produce a solid pharmaceutical dosage form comprising a network of the carrier material carrying a unit dosage of pharmaceutical substance which process comprises freeze drying the composition in an apparatus as claimed in any one of Claims 1 to 5.

7. A freeze dryer apparatus substantially as hereinbefore described with reference to and as illustrated in the accompanying drawing.

8. A process for treeze drying a composition substantially as hereinbefore described with reference to any one of the Examples.

9, A freeze dried product whenever prepared by a process as claimed in Claim 6 or 8 or whenever freeze dried in an apparatus as claimed in any one of Claims 1 to 5 and 7.