Method for monitoring primary drying of a freeze-drying process

• US 9,170,049 B2
• Filed: 12/22/2010
• Issued: 10/27/2015
• Est. Priority Date: 12/23/2009
• Status: Active Grant

• Current Assignee: Azbil Telstar Technologies SL
• Original Assignee: Azbil Telstar Technologies SL
• Inventors: Fissore, Davide, Pisano, Roberto, Barresi, Antonello A.
• Primary Examiner(s): GRAVINI, STEPHEN MICHAEL
• Application Number:
  US13/518,445
• Publication Number:
  US 20130006546A1
• Time in Patent Office: 1,770 Days
• Field of Search: 342/84, 342/87, 342/98, 165/65, 236/12.12
• US Class Current: 1/1
• CPC Class Codes: F26B 5/06 the process involving freezing

Abstract

A freeze-drying process includes a primary drying phase. Within this phase, a test is performed for causing a variation of partial pressure of solvent inside a drying chamber. At the beginning of the test, a product sublimation flux, a total pressure and a partial pressure of the solvent in the drying chamber are measured. A product temperature is estimated at the interface of sublimation at the beginning of the test. The solvent vapor pressure at the interface of sublimation is calculated as is a resistance of a dried layer of the product to the vapor flow of the solvent. Next, a thickness of a frozen layer of the product is calculated and a coefficient of heat transfer between heating surface and product is also calculated. An initial temperature profile of the frozen product is then calculated as is a total pressure in the drying chamber. A value of the product temperature at the interface of sublimation at the beginning of test is determined and a time constant of the freeze-drying process is calculated.

Claims

1. A method for monitoring a primary drying phase of a freeze-drying process in a freeze-drying apparatus that includes a drying chamber provided with at least one controlled-temperature heating surface for supporting a product to be freeze-dried, said product including at least one solvent, in particular water, said method comprising the following steps:

performing a test that is suitable for causing a variation of partial pressure of solvent inside said drying chamber (step

     0);

at the beginning of said test (t=t₀) measuring a sublimation flux (j_w,0) of said product, a total pressure (p_c,0) in said drying chamber and a partial pressure of said solvent (p_w,c,0) in said drying chamber (step

     1);

estimating a temperature of said product at the interface of sublimation (T_i0) at the beginning of said test (step

     2);

calculating the vapour pressure of said solvent at the interface of sublimation (p_w,i) (step

     3);

calculating a resistance of a dried layer of said product to the vapour flow of said solvent (R_p) (step

     4);

calculating a thickness of a frozen layer of said product (L_f) (step

     5);

calculating a coefficient of heat transfer (K_v) between the heating surface and the product (step

     6);

calculating a temperature profile of the frozen product (T|_t0) at the beginning of said test (step

     7);

calculating a total pressure (p_c) in said drying chamber (step

     8);

determining a value of the product temperature at the interface of sublimation at the beginning of said test (T_i0) that best fits the calculated value of the total pressure in the drying chamber (p_c) and the measured value of the total pressure in the drying chamber (p_c,meas) (step

     9); and

calculating a time constant (t) of the freeze-drying process (step

     10),

wherein said sublimation flux of said solvent is measured directly, in particular using one between;

a windmill sensor positioned in a conduit connecting said drying chamber to a condensation chamber of the freeze-drying apparatus;

a Tunable Diode Laser Absorption Spectroscopy (TDLAS);

an optical spectrometer in said drying chamber;

a fast-dynamics moisture sensor (with measurements at different points of the apparatus);

a thermal-conducting or Pirani-type pressure sensor in addition to a capacitive pressure sensor used for measuring total pressure.

2. A method according to claim 1, and further comprising, after calculating said time constant (t), the step of calculating (step 11):

temperature of the frozen layer at the beginning of said test (T|_t=0);

temperature trend (T=T(z)) of said product during said test;

thickness of the frozen layer (L_f);

resistance of the dried layer (R_p);

coefficient of heat transfer (K_v).

3. A method according to claim 2, wherein said initial temperature value of the product frozen layer (T|t=0) at the beginning of said test is calculated by using the equation:

4. A method according to claim 2, wherein said temperature trend T=T(z) of the product during said test is calculated by using the equations:

5. A method according to claim 1, wherein said resistance of the dried layer of said product to the vapour flow of said solvent (R_p) is calculated by using the equation:

6. A method according to claim 1, wherein said thickness of a frozen layer (Lf) is calculated by using the equation:

7. A method according to claim 1, wherein said coefficient of heat transfer (Kv) is calculated by using the equation:

8. A method according to claim 1, wherein said test that is suitable for causing a variation of partial pressure is a Pressure Rise Test (PRT) in said drying chamber.

9. A method according to claim 8, wherein said total pressure (p_c) in said drying chamber is calculated by using the equation:

p_c=p_w,c+p_in,c=p_w,c+F_leakt+p_in,c,0 for t≧

t₀ 

 

(eq.

     10)

where;

p_c;

total pressure in the drying chamber, [Pa]

p_w,c;

partial pressure of said solvent in the drying chamber, [Pa]

p_in,c;

partial pressure of inert gas in the drying chamber, [Pa]

p_in,c,0;

partial pressure of inert gas in the drying chamber at the beginning of the test, [Pa]

t;

time, [s]

F_leak;

leakage rate, [Pa s<sup>−

1</sup>].

10. A method according to claim 9, wherein said determining a value of the temperature of the product at the interface of sublimation at the beginning of said test (T_i0) (step 9) further comprises the step of integrating a discretised system of ordinary differential equations (ODE) comprising the following equations in the time interval (t₀, t_f), where t_f−

t₀ is the time duration of said test;

11. A method according to claim 1, wherein said test that is suitable for causing a variation of partial pressure comprises:

adjusting a temperature of said heating surface by a set value;

or

adjusting the value set in the controller of the pressure in the drying chamber;

or

if a controlled flowrate of inert gas is used for controlling total pressure in the drying chamber, stopping for a short time the flow of inert gas introduced into said drying chamber;

or

if a valve is used that connects a condensation chamber of said freeze-drying apparatus to a vacuum pump for controlling the pressure in said drying chamber, closing said valve for a short interval of time.

12. A method according to claim 11, wherein said total pressure (p_c) in said drying chamber is calculated by using the equation:

13. A method according to claim 12, wherein said determining a value of the temperature of the product at the interface of sublimation at the beginning of said test (T_i0) (step 9) further comprises the step of integrating a discretised system of ordinary differential equations (ODE) comprising the following equations in the interval of time (t₀, t_f), where t_f−

t₀ is the time duration of said test;

14. A method according to claim 10, wherein said determining said value of the temperature of the product at the interface of sublimation at the beginning of said test (T_i0) (step 9) further comprises, after said integrating, the step of solving a non-linear least-square optimization problem, in particular looking for a value that minimises an objective function (ƒ

);

15. A method according to claim 13, wherein said determining said value of the temperature of the product at the interface of sublimation at the beginning of said test (T_i0) (step 9) further comprises, after said integrating, the step of solving a non-linear least-square optimization problem, in particular looking for a value that minimises an objective function (ƒ

);

16. A method according to claim 10, wherein said time constant (t) of said freeze-drying process is calculated by the equation:

17. A method according to claim 13, wherein said time constant (t) of said freeze-drying process is calculated by the equation:

18. A method according to claim 16, wherein said pressure rise test (PRT) has optimal duration that is substantially equal to said time constant (t).

22. A method according to claim 2, comprising repeating at least steps 0 to 11 at preset intervals.

19. A method for monitoring a primary drying phase of a freeze-drying process in a freeze-drying apparatus that includes a drying chamber provided with at least one controlled-temperature heating surface for supporting a product to be freeze-dried, said product including at least one solvent, in particular water, said method comprising the following steps:

performing a test that is suitable for causing a variation of partial pressure of solvent inside said drying chamber (step

     0);

at the beginning of said test (t=t₀) measuring a sublimation flux (j_w,0) of said product, a total pressure (p_c,0) in said drying chamber and a partial pressure of said solvent (p_w,c,0) in said drying chamber (step

     1);

estimating a temperature of said product at the interface of sublimation (T_i0) at the beginning of said test (step

     2);

calculating the vapour pressure of said solvent at the interface of sublimation (p_w,i) (step

     3);

calculating a resistance of a dried layer of said product to the vapour flow of said solvent (R_p) (step

     4);

calculating a thickness of a frozen layer of said product (L_f) (step

     5);

calculating a coefficient of heat transfer (K_v) between the heating surface and the product (step

     6);

calculating a temperature profile of the frozen product (T|_t0) at the beginning of said test (step

     7);

calculating a total pressure (p_c) in said drying chamber (step

     8);

determining a value of the product temperature at the interface of sublimation at the beginning of said test (T_i0) that best fits the calculated value of the total pressure in the drying chamber (p_c) and the measured value of the total pressure in the drying chamber (p_c,meas) (step

     9); and

calculating a time constant (t) of the freeze-drying process (step

     10),

wherein said sublimation flux of said solvent is measured indirectly, calculated from pressure measurements inside said drying chamber conducted during said test.

20. A method according to claim 19, wherein the sublimation flux (j_w,0) of said solvent at the beginning of said PRT is calculated by using the equation:

21. A method according to claim 20, wherein said product to be freeze-dried comprises a plurality of solvents and a sublimation flux (j_solv,r,0) of each solvent at the beginning of said test is calculated by using the equation:

23. A method comprising performing a primary drying phase of a freeze-drying process for freeze-drying a product to be freeze-dried in a freeze-drying apparatus that includes a drying chamber provided with at least one controlled-temperature heating surface for supporting a product to be freeze-dried, said product including at least one solvent, in particular water, said method comprising during said primary drying phase the following steps:

performing a test that is suitable for causing a variation of partial pressure of solvent inside said drying chamber (step

     0);

at the beginning of said test (t=t₀) measuring a sublimation flux (j_w,0) of said product, a total pressure (p_c,0) in said drying chamber and a partial pressure of said solvent (p_w,c,0) in said drying chamber (step

     1);

estimating a temperature of said product at the interface of sublimation (T_i0) at the beginning of said test (step

     2);

calculating the vapour pressure of said solvent at the interface of sublimation (p_w,i) (step

     3);

calculating a resistance of a dried layer of said product to the vapour flow of said solvent (R_p) (step

     4);

calculating a thickness of a frozen layer of said product (L_f) (step

     5);

calculating a coefficient of heat transfer (K_v) between heating surface and product (step

     6);

calculating a temperature profile of the frozen product (T|_t0) at the beginning of said test (step

     7);

calculating a total pressure (p_c) in said drying chamber (step

     8);

determining a value of the product temperature at the interface of sublimation at the beginning of said test (T_i0) that best fits the calculated value of the total pressure in the drying chamber (p_c) and the measured value of the total pressure in the drying chamber (p_c,meas) (step

     9);

calculating a time constant (τ

) of the freeze-drying process (step

     10),

wherein said sublimation flux of said solvent is measured directly, in particular using one between;

a windmill sensor positioned in a conduit connecting said drying chamber to a condensation chamber of the freeze-drying apparatus;

a Tunable Diode Laser Absorption Spectroscopy (TDLAS);

an optical spectrometer in said drying chamber;

a fast-dynamics moisture sensor (with measurements at different points of the apparatus);

a thermal-conducting or Pirani-type pressure sensor in addition to a capacitive pressure sensor used for measuring total pressure.

24. A method for performing a primary drying phase of a freeze-drying process for freeze-drying a product to be freeze-dried in a freeze-drying apparatus that includes a drying chamber provided with at least one controlled-temperature heating surface for supporting a product to be freeze-dried, said product including at least one solvent, in particular water, said method comprising during said primary drying phase the following steps:

performing a test that is suitable for causing a variation of partial pressure of solvent inside said drying chamber (step

     0);

at the beginning of said test (t=t₀) measuring a sublimation flux (j_w,0) of said product, a total pressure (p_c,0) in said drying chamber and a partial pressure of said solvent (p_w,c,0) in said drying chamber (step

     1);

estimating a temperature of said product at the interface of sublimation (T_i0) at the beginning of said test (step

     2);

calculating the vapour pressure of said solvent at the interface of sublimation (p_w,i) (step

     3);

calculating a resistance of a dried layer of said product to the vapour flow of said solvent (R_p) (step

     4);

calculating a thickness of a frozen layer of said product (L_f) (step

     5);

calculating a coefficient of heat transfer (K_v) between heating surface and product (step

     6);

calculating a temperature profile of the frozen product (T|_t0) at the beginning of said test (step

     7);

calculating a total pressure (p_c) in said drying chamber (step

     8);

determining a value of the product temperature at the interface of sublimation at the beginning of said test (T_i0) that best fits the calculated value of the total pressure in the drying chamber (p_c) and the measured value of the total pressure in the drying chamber (p_c,meas) (step

     9);

calculating a time constant (τ

) of the freeze-drying process (step

     10),

wherein said sublimation flux of said solvent is measured indirectly, calculated from pressure measurements inside said drying chamber conducted during said test.