GB2551687A - Freeze drying apparatus - Google Patents
Freeze drying apparatus Download PDFInfo
- Publication number
- GB2551687A GB2551687A GB1603772.3A GB201603772A GB2551687A GB 2551687 A GB2551687 A GB 2551687A GB 201603772 A GB201603772 A GB 201603772A GB 2551687 A GB2551687 A GB 2551687A
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- Prior art keywords
- vial
- freeze drying
- chamber
- optical
- sample
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Classifications
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/06—Means for illuminating specimens
- G02B21/08—Condensers
- G02B21/10—Condensers affording dark-field illumination
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/044—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum for drying materials in a batch operation in an enclosure having a plurality of shelves which may be heated
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B9/00—Machines or apparatus for drying solid materials or objects at rest or with only local agitation; Domestic airing cupboards
- F26B9/06—Machines or apparatus for drying solid materials or objects at rest or with only local agitation; Domestic airing cupboards in stationary drums or chambers
- F26B9/066—Machines or apparatus for drying solid materials or objects at rest or with only local agitation; Domestic airing cupboards in stationary drums or chambers the products to be dried being disposed on one or more containers, which may have at least partly gas-previous walls, e.g. trays or shelves in a stack
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- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Drying Of Solid Materials (AREA)
Abstract
A freeze drying or lyophilisation device comprises a chamber 1 having a temperature shelf 11 upon which one or more vials 7 containing a sample 8 may be located. A cold trap 13 and a means 19 to control the chamber pressure and control the shelf temperature FIG 2 43, 45 are provided. The chamber is fitted with a side window 3 to provide optical images of the chamber contents. The images may be obtained using microscopes 23, 51 employing darkfield illumination. Focussing 27 and translation movement means 29 may be provided for the microscopes, image sensors 30 may be supplied A second window 33 may be fitted to allow images in a vertical axis 9 to be seen. A manipulator 31 may be provided to move vials in the chamber. The device is intended for use in small batch research and development and may be bench or table top mounted. The microscope may be used to view movement of the sublimation front as the chamber cools.
Description
(54) Title of the Invention: Freeze drying apparatus
Abstract Title: Freeze drying apparatus with optical viewing system (57) A freeze drying or lyophilisation device comprises a chamber 1 having a temperature shelf 11 upon which one or more vials 7 containing a sample 8 may be located. A cold trap 13 and a means 19 to control the chamber pressure and control the shelf temperature FIG 2 43, 45 are provided. The chamber is fitted with a side window 3 to provide optical images of the chamber contents. The images may be obtained using microscopes 23, 51 employing darkfield illumination. Focussing 27 and translation movement means 29 may be provided for the microscopes, image sensors 30 may be supplied A second window 33 may be fitted to allow images in a vertical axis 9 to be seen. A manipulator 31 may be provided to move vials in the chamber. The device is intended for use in small batch research and development and may be bench or table top mounted. The microscope may be used to view movement of the sublimation front as the chamber cools.
(13)
Figure 1
1/2
Figure 1
212
Figure 2
Apparatus and method to study and optimise the process of freeze drying
Technical background and problem description
This invention relates to an apparatus and a method that is used to study and optimise the process of freeze drying. Freeze drying itself has many applications in the pharmaceutical sector as well as in the food industry.
Many pharmaceutical products or ingredients require freeze drying to enable long-term storage or transport. This is typically performed inside standard pharmaceutical vials, which are cylindrical glass containers that can be closed and sealed with a stopper or similar mechanism. On an industrial scale freeze drying is undertaken in machines with a shelf space of up to several tens of square meters. Smaller freeze dryer systems with less shelf space are available in the form of table-top or freestanding research and scale-up units [1] for use with standard vials [2], Although these units can be used for the development of production freeze-drying processes it is costly to fill a large number of vials with the expensive pharmaceutical substances for freeze-drying test runs. To obtain accurate data from such freeze dryers the shelving space needs Furthermore such larger run is also timeconsuming and allows only to collect limited data during a test run, for example from the use of dipping temperature sensors. Running just a few or indeed a single vial in such a relatively large unit is typically not done because more than half the shelf space needs to be loaded in order to obtain an accurate representation of the larger scale process.
On the other hand a different small size of instrument for process development is a freeze-drying microscopy system, such as the Linkam FDCS196 [3], Here a very small sample volume mounted between two coverslips (glass plates) is used but the technique has some limitations: the layer-like arrangement of the sample may not fully model the behaviour of the bulk material inside a vial under industrial conditions and the sample volume is not accessible for further analysis, such as Karl Fischer titration, DSC analysis or reconstitution analysis.
The method and apparatus disclosed in this document allow to perform freeze drying of samples in a typical bulk configuration inside a standard pharmaceutical vial while using optical imaging and optional in-situ monitoring techniques - while also making the freeze dried samples available for subsequent analysis and reducing the amount of pharmaceutical product needed compared to typical pilot freeze drying systems. The process parameters obtained and iterated with the instrument and method disclosed can be up-scaled and transferred to larger facilities.
Description of the invention
The invention disclosed here allows to observe and analyse the process of freeze drying inside a standard pharmaceutical vial [2], which is a small cylindrical glass container - typically with the option to be closed with a rubber plug.
In the following, we refer to figure 1 to discuss the principal components of the apparatus according to the invention to study the process of freeze drying. Figure 1 shows the a freeze drying chamber in a cross section view. Provided is a freeze drying chamber (1) with an optical side window (3). In a preferred embodiment the optical side window (3) has an optical coating that reflects thermal radiation from within the chamber while transmitting the wavelengths used for imaging. This measure allows to reduce heat losses in the vicinity of the optical side window (3). The vial (7) is resting on the temperature controlled shelf (11) where the axis if symmetry of the vial (9) is substantially vertical. Furthermore, there is a cold trap unit (13) provided in the freeze drying chamber (1). The purpose of (13) is to condense moisture inside the atmosphere of the freeze drying chamber (1) in order to facilitate the drying process. Under typical operating conditions the temperature of the cold trap unit (13) will be significantly below that of the temperature controlled shelf (11). The controller unit (15) is directly linked to the pressure control valve (19) and the pressure sensor system (21) in order to control the pressure within the freeze drying chamber (1).
The side imaging system (23) is an optical system provided for imaging of the sample (8) inside the vial (7) during the process of freeze drying. The side imaging system (23) is now discussed in more detail. The optical axis of the side imaging system (25) is substantially perpendicular to the axis of symmetry of the vial (9) and these two axes substantially intersects each other. The one or more wavelengths used for the imaging are compatible with the transmission characteristics of the optical side window (3). Focal adjustment means (27) of the side imaging system (23) allow to shift the focal position along the optical axis of the side imaging system (25). This way the system can be configured to focus near the interface between the sample (7) and the vial (7) or deeper into the sample (8). During freeze drying the sublimation front, which is the location of the interface within the sample (8) where the sublimation process happens, is travelling in a substantially vertical direction. There is a vertical imaging position adjustment means (29) provided with the side imaging system (23). This allows to vertically translate the field of view of the side imaging system (23) to follow the travel of the sublimation front, if necessary. The unit (29) can be driven manually or use automated motorised components.
In a preferred embodiment of the invention the side imaging system (23) uses darkfield illumination in order to avoid reflections from the optical side window (3) or the vial (7). Preferably the optical element of the side imaging system (23) closest to the optical window (3) is a darkfield version of a microscope objective lens [4j. This allows detailed high resolution optical observation of the process. Furthermore, the unit (23) comprises an imaging sensor (30). Within a typical embodiment this will be an area sensor based CCD or CMOS technology.
In a method according to the invention the image data from the imaging sensor (30) is automatically analysed by means of software algorithms in order to locate the position of the sublimation front. Capturing image data at known time intervals and extracting the corresponding positions of the respective sublimation fronts allows to calculate the speed of the sublimation front and the rate of sublimation.
Referring to figure 1, we will now discuss a second imaging system, the top imaging system (51). This system also features an image detector (30) and images a substantially horizontal plane, which can be adjusted to coincide with the top surface of the sample within the vial. The imaging path of the top imaging system (51) also comprises the optical top window (33). This top imaging system (51) is used to study the process of controlled nucleation in more detail. In a typical configuration, the vial (7) will be positioned on the temperature controlled shelf (11) such that the optical axis of the top imaging system (51) is substantially aligned with the axis of symmetry of the vial. The vial manipulator unit (31) as shown in figure 1 also serves to position and align the vial (7) with the top imaging system (51). The top imaging system (51) can only be used if there is a clear optical path between the optical top window (33) and the aperture of the vial (7). Therefore no standard stopper or other form of closing and sealing of the vial can be used.
According to one aspect of the invention a specially designed vial stopper is used, where the vial stopper has a transparent stopper window on the top. Because of the stopper window the top imaging system (51) can image inside the vial despite the use of the stopper, which may be required for other subsequent parts of the process.
The temperature controlled shelf (11) is shown in greater detail in figure 2. It comprises a shelf temperature sensor (41), a shelf electrical heating element (43) and a shelf cooling loop (45). All elements (41), (43) and (45) are connected to the controller unit (15). The controller unit (15) contains an electrical driver unit as well as a pump to draw liquid nitrogen through the shelf cooling loop (45). With the information from the shelf temperature sensor (41) the controller unit (15) can balance the electrical heating power delivered to the shelf electrical heating element (43) with the cooling power provided by the shelf cooling loop (45) and achieve closed loop control of the temperature of the temperature controlled shelf (11). The shelf cooling loop (45) is separated from the atmosphere of the freeze drying chamber (1).
The cold trap (13) is shown in greater detail in figure 2. It comprises a cold trap temperature sensor (47) and a cold trap cooling loop (49). The elements (47) and (49) are connected to the controller unit (15). The controller unit (15) contains a pump to draw liquid nitrogen through the cold trap cooling loop (49). With the information from the cold trap temperature sensor (47) the controller unit (15) can monitor and / or control the cooling power provided by the cold trap cooling loop (49). The cold trap cooling loop (49) is separated from the atmosphere of the freeze drying chamber (1).
In a method for studying the process of freeze drying according to the invention the temperatures for the temperature controlled shelf (11), the cold trap (13) as well as the pressure in the freeze drying chamber (1) can be programmed to define a freeze drying cycle. Additional optional process features, such as controlled nucleation, can be used to further refine the process.
Controlled nucleation is a way to influence the freezing process and will now be discussed in further detail. Controlled nucleation inside the vial (7) can be achieved by introducing small ice crystals into the vial when the temperature of the solution to be frozen inside the vial (7) is slightly below the thermodynamic freezing temperature. The inlet port (35) can be opened and closed by means of a valve and can be used to introduce a gas carrying ice crystals into the freeze drying chamber (1). An example for providing gas for the controlled nucleation can be found in [5], The adjustable gas outlet nozzle (37) is located in the vicinity of the aperture of the vial (7). When working with vials it is common that the plug, often also called stopper, which will eventually seal the vial, is pushed half way in, leaving an effective aperture open. In this case the gas outlet nozzle (37) is placed in the vicinity of the effective aperture.
In a method according to the invention to study freeze drying in a vial, especially to study the controlled nucleation aspect of freeze drying, composition and flow rate of the gas dispensed from the gas outlet nozzle (37) are controlled in order to steer the parameters of the controlled nucleation. The top imaging system (51) is used to monitor the process of controlled nucleation inside the vial (7).
The freeze drying chamber (1) is operated within a pressure from atmospheric pressure down to approximately 20 mTorr. The pump (17), the pressure control valve (19), the pressure sensor (21) and the controller unit (15) are jointly used to control the pressure inside the freeze drying chamber (1).
A vial (7) or a small group of vials is placed inside the freeze drying chamber (1). Typical group sizes are below ten vials. The freeze drying chamber is fitted with a pressure sensor system (21). This sensor system comprises a Pirani-type pressure sensor and / or a capacitive pressure sensor and data from the pressure sensor system (21) can be used for controlling the chamber pressure as well as obtaining process parameters. If different sensor types are used in the unit (21), such as Pirani and CM types, the difference between the readings of these sensor types does also contain information about the freeze drying process cycle and can be used for process analysis and control.
An advantage of the method according to the invention is that the freeze dried samples inside one or more vials (7) can be made and monitored in a relatively small batch at a relatively low cost and allow subsequent analysis with complementing methods, including but not limited to: Karl Fischer titration, differential scanning calorimetry (DSC) and reconstitution analysis. The process parameters obtained and iterated with the instrument and method disclosed can be up-scaled and transferred to larger facilities.
List of elements referenced in the figures
| (1) | Freeze drying chamber |
| (3) | Optical side window |
| (5) | Optical coating |
| (7) | Vial |
| (8) | Sample |
| (9) | Axis of symmetry of the vial |
| (11) | Temperature controlled shelf |
| (13) | Cold trap unit |
| (15) | Controller unit |
| (17) | Pump |
| (19) | Pressure control valve |
| (21) | Pressure sensor system |
| (23) | Side imaging system |
| (25) | Optical axis of the side imaging system |
| (27) | Focal adjustment means |
| (29) | Vertical imaging position adjustment means |
| (30) | Image sensor |
| (31) | Vial manipulator unit |
| (33) | Optical top window |
| (35) | Inlet port |
| (37) | Gas outlet nozzle |
| (41) | Shelf Temperature sensor |
| (43) | Shelf electrical heating element |
| (45) | Shelf cooling loop |
| (47) | Cold trap temperature sensor |
| (49) | Cold trap cooling loop |
| (51) | Top imaging system |
Literature references [1] http://biopharma.cj3.uk/bps/freeze-drving/fr&ez&-drv'&rs/research-sc3l&-up-fr&&z&-dryers/ (accessed in February 29, 2016) [2] htt£ZZwww.schprtcom/ehamTaceuflcaLfiackagi^^ (accessed
February 29, 2016) [3] Linkam FDCS196 system: http://www.iinkain.co.uk/fdcsl96-features/ (accessed February 29, 2016) [4] Darkfield imaging in reflected light: http://www.Olympus ip/js.gom/en/micrpscope/ternjs/featurel4/ (accessed February 29, 2016) [5] US 8875413 B2, Ling, Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice crystal distribution from condensed frost
Apparatus and method to study and optimise the process of freeze drying
05 17
Claims (13)
1. Apparatus to study and optimise the process of freeze drying, comprising a freeze drying chamber with a temperature controlled shelf, one vial or a small group of vials resting on the temperature controlled shelf, a sample within one or more vials, a cold trap unit in connection with the volume of the freeze drying chamber and means to control the chamber pressure and the temperature of the temperature controlled shelf, where a side optical window is fitted to the chamber and a side optical system provides highresolution optical images of the sample inside the vial through the optical side window.
2. Apparatus according to claim 1, where the side optical system is equipped with a darkfield illumination layout that illuminates the sample inside the vial.
3. Apparatus according to claim 1, where the side optical system comprises an imaging sensor.
4. Apparatus according to claim 1, where the side optical system has adjustment means to adjust focus and / or position of the field of view on the sample.
5. Apparatus according to claim 1, where a top optical window is fitted to the chamber and the top optical system provides high-resolution optical images of the sample inside the vial through top optical window.
6. Apparatus according to claim 1, where the side optical system has focal adjustment means and vertical image position adjustment means.
7. Apparatus according to claim 1, where a vial manipulator unit is provided and allows to position the vial inside the freeze drying chamber.
8. Method to study and optimise the process of freeze drying, using a freeze drying chamber with a temperature controlled shelf, with one vial or a small group of vials resting on the temperature controlled shelf, a sample within one more vials, an optical side window, a cold trap unit in connection with the volume of the freeze drying chamber and means to control the chamber pressure and the temperature of the temperature controlled shelf, where the high-resolution optical image information from a side optical system is used to monitor and / or control process conditions of the sample inside the vial.
9. Method according to claim 8, where the side imaging system uses darkfield illumination.
10. Method according to claim 8, where the side imaging system is moved vertically to translate the field of view and is moved horizontally to adjust focus.
11. Method according to claim 8, where the high-resolution optical image information from the side image optical system is analysed automatically for the purpose of process analysis and / or control.
12. Method according to claim 8, where a vial manipulator unit positions the vial inside the freeze drying chamber.
13. Method according to claim 8, where the top optical system images the sample in a vial inside the freeze drying chamber through the top optical window, where the high-resolution optical image information from the top optical system is used to monitor and / or control process conditions of the sample inside the vial.
02 05 17
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Application No: GB1603772.3
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1603772.3A GB2551687A (en) | 2016-03-04 | 2016-03-04 | Freeze drying apparatus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1603772.3A GB2551687A (en) | 2016-03-04 | 2016-03-04 | Freeze drying apparatus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB201603772D0 GB201603772D0 (en) | 2016-04-20 |
| GB2551687A true GB2551687A (en) | 2018-01-03 |
Family
ID=55859012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1603772.3A Withdrawn GB2551687A (en) | 2016-03-04 | 2016-03-04 | Freeze drying apparatus |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2551687A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1423353A (en) * | 1972-06-19 | 1976-02-04 | Boc International Ltd | Vacuum lock |
| CN1818738A (en) * | 2006-03-10 | 2006-08-16 | 浙江大学 | Microscope observation system during freezing dry process |
| WO2011120342A1 (en) * | 2010-04-02 | 2011-10-06 | 中山大学 | Vacuum freeze-drying apparatus |
-
2016
- 2016-03-04 GB GB1603772.3A patent/GB2551687A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1423353A (en) * | 1972-06-19 | 1976-02-04 | Boc International Ltd | Vacuum lock |
| CN1818738A (en) * | 2006-03-10 | 2006-08-16 | 浙江大学 | Microscope observation system during freezing dry process |
| WO2011120342A1 (en) * | 2010-04-02 | 2011-10-06 | 中山大学 | Vacuum freeze-drying apparatus |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201603772D0 (en) | 2016-04-20 |
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| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |