IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0518445
(2010-12-22)
|
등록번호 |
US-9170049
(2015-10-27)
|
우선권정보 |
IT-MO2009A0309 (2009-12-23) |
국제출원번호 |
PCT/IB2010/056011
(2010-12-22)
|
§371/§102 date |
20120919
(20120919)
|
국제공개번호 |
WO2011/077390
(2011-06-30)
|
발명자
/ 주소 |
- Fissore, Davide
- Pisano, Roberto
- Barresi, Antonello A.
|
출원인 / 주소 |
- Azbil Telstar Technologies, S.L.
|
대리인 / 주소 |
Laubscher Spendlove & Laubscher, P.C.
|
인용정보 |
피인용 횟수 :
1 인용 특허 :
10 |
초록
▼
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 dryi
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.
대표청구항
▼
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 part
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 (jw,0) of said product, a total pressure (pc,0) in said drying chamber and a partial pressure of said solvent (pw,c,0) in said drying chamber (step 1);estimating a temperature of said product at the interface of sublimation (Ti0) at the beginning of said test (step 2);calculating the vapour pressure of said solvent at the interface of sublimation (pw,i) (step 3);calculating a resistance of a dried layer of said product to the vapour flow of said solvent (Rp) (step 4);calculating a thickness of a frozen layer of said product (Lf) (step 5);calculating a coefficient of heat transfer (Kv) 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 (pc) in said drying chamber (step 8);determining a value of the product temperature at the interface of sublimation at the beginning of said test (Ti0) that best fits the calculated value of the total pressure in the drying chamber (pc) and the measured value of the total pressure in the drying chamber (pc,meas) (step 9); andcalculating 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 (Lf);resistance of the dried layer (Rp);coefficient of heat transfer (Kv). 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: Tt0=Ti,0+zλfΔHsjw,0for0≤z≤Lf(eq.4)where:T|t0: temperature of the frozen product at the beginning of said test, [K]Ti0: temperature of the product at the interface of sublimation at the beginning of said test, [K]z: axial coordinates in the product thickness, [m]lf: thermal conductivity of the frozen layer, [J s−1m−1K−1]. 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: ∂T∂t=λfρfcp,f∂2T∂z2fort>t0,0≤z≤Lf(eq.3)Tt0=Ti,0+zλfΔHsjw,0for0≤z≤Lf(eq.4)λf∂T∂tz=0=ΔHsjwfort≥t0(eq.5)λf∂T∂zz=Lf=Kv(Ts-Tb)fort≥t0(eq.6)where:T: temperature of the product, [K]t: time, [s]lf: thermal conductivity of the frozen layer, [J s−1m−1K−1]rf: density of the frozen layer, [kg m−3]cp,f: specific heat of the frozen layer, [J kg−1K−1]t0: time at beginning of test, [s]z: axial coordinate of the product, [m]Lf: thickness of the frozen layer, [m]T|t0: temperature of the frozen product at the beginning of said test, KTi,0: temperature of the product at the interface of sublimation (z=0) at beginning of PRT test, [K]DHs: heat of sublimation, [J kg−1]jw,0: sublimation flux (jw,0) of said product at the beginning of the test, [kg s−1m−2]Kv: coefficient of heat transfer between heating surface and product, [J s−1 s−1K−1m−2]Ts: temperature of the heating surface, [K]Tb: temperature of the product near to the bottom of a container of said product (z=Lf), [K]. 5. A method according to claim 1, wherein said resistance of the dried layer of said product to the vapour flow of said solvent (Rp) is calculated by using the equation: Rp=pw,i,0-pw,c,0jw,0(eq.16)where:Rp: resistance of the dried layer to the vapour flow of said solvent, [m s−1]pw,i,0: vapour pressure of said solvent at the interface of sublimation at the beginning of said Pa test. 6. A method according to claim 1, wherein said thickness of a frozen layer (Lf) is calculated by using the equation: Lf=Lf(-1)-1(ρf-ρd)∫t0(-1)t01Rp(pw,i-pw,c)ⅆt(eq.18)where:Lf: thickness of the frozen layer, [m]pw,i: vapour pressure of said solvent at the interface of sublimation, [Pa]pw,c: partial pressure of said solvent in the drying chamber, [Pa]rf: density of the frozen layer, [kg m−3]rd: apparent density of the dried layer, [kg m−3]Rp: resistance of the dried layer to the vapour flow of said solvent, [m s−1]t: time, [s]t0: time of beginning of test, [s]and where the apex “−1” refers to quantities calculated or measured at time t=t0(−1). 7. A method according to claim 1, wherein said coefficient of heat transfer (Kv) is calculated by using the equation: Kv=[Ts-Ti,0ΔHsjw,0-Lfλf]-1(eq.7)where:Kv: coefficient of heat transfer between heating surface and product, [J s−1K−1m−2]Ts: temperature of the heating surface, [K]Ti,0: temperature of the product at the interface of sublimation at the beginning of said test, [K]DHs: heat of sublimation, [J kg−1]jw,0: sublimation flux at the beginning of the test, [kg s−1 m−2]Lf: thickness of the frozen layer, [m]lf: thermal conductivity of the frozen layer, [J s−1m−1K−1]. 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 (pc) in said drying chamber is calculated by using the equation: pc=pw,c+pin,c=pw,c+Fleakt+pin,c,0 for t≧t0 (eq. 10)where:pc: total pressure in the drying chamber, [Pa]pw,c: partial pressure of said solvent in the drying chamber, [Pa]pin,c: partial pressure of inert gas in the drying chamber, [Pa]pin,c,0: partial pressure of inert gas in the drying chamber at the beginning of the test, [Pa]t: time, [s]Fleak: leakage rate, [Pa s−1]. 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 (Ti0) (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, tf), where tf−t0 is the time duration of said test: ∂T∂t=λfρfcp,f∂2T∂z2fort>t0,0≤z≤Lf(eq.3)(MwVcRTc)ⅆpw,cⅆt=As,t1Rp(pw,i-pw,c)(eq.8)where:T: temperature of the product, [K]t: time, [s]lf: thermal conductivity of the frozen layer, [J s−lm−1K−1]rf: density of the frozen layer, [kg m−3]cp,f: specific heat of the frozen layer, [J kg−1K−1]t0: time at beginning of PRT, [s]z: axial coordinate of the product, [m]Mw: molecular mass of said solvent, [kg mol−1]Vc: volume of the drying chamber, [m3]R: ideal gas constant, [J K−1mol−1]Tc: temperature of the vapour in the drying chamber, [K]As,t: area of the interface of sublimation, [m2]Rp: resistance of the dried layer to the vapour flow, [m s−1]pw,i: vapour pressure of said solvent at the interface of sublimation, [Pa]pw,c: partial pressure of said solvent in the drying chamber, [Pa]. 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; oradjusting the value set in the controller of the pressure in the drying chamber; orif 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; orif 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 (pc) in said drying chamber is calculated by using the equation: ⅆpcⅆt=ⅆpw,cⅆt+ⅆpin,cⅆt(eq.38)where:pc: total pressure in the drying chamber, [Pa]pw,c: partial pressure of said solvent in the drying chamber, [Pa]pin,c: partial pressure of inert gas in the drying chamber, [Pa]t: time, [s]. 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 (Ti0) (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, tf), where tf−t0 is the time duration of said test: ∂T∂t=λfρfcp,f∂2T∂z2fort>t0,0≤z≤Lf(eq.3)(MwVcRTc)ⅆpw,cⅆt=AS,t1Rp(pw,i-pw,c)-yw,cFcond(eq.37)where:T: temperature of the product, [K]t: time, [s]lf: thermal conductivity of the frozen layer, [J s−1m−1K−1]rf: density of the frozen layer, [kg m−3]cp,f: specific heat of the frozen layer, [J kg−1K−1]t0: time at beginning of PRT, [s]Mw: molecular mass of said solvent, [kg mol−1]Vc: volume of the drying chamber, [m3]R: ideal gas constant, [J K−1mol−1]Tc: temperature of the vapour in the drying chamber, [K]As,t: area of the interface of sublimation, [m2]Rp: resistance of the dried layer to the vapour flow, [m s−1]pw,i: vapour pressure of said solvent at the interface of sublimation, [Pa]pw,c: partial pressure of said solvent in the drying chamber, [Pa];Fcond: total gas flowrate that goes from the drying chamber to the condensation chamber, [mol s−1]yw,c: molar fraction of solvent inside the drying chamber. 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 (Ti0) (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): f(Ti,0)=∑k(pc,k-pc,meas,k)2(eq.19)wherepc,k: calculated value of the total pressure in the drying chamber at the instant k during said test, [Pa]pc,meas,k: measured total pressure in the drying chamber measured at the instant k during said test, [Pa]. 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 (Ti0) (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): f(Ti,0)=∑k(pc,k-pc,meas,k)2(eq.19)wherepc,k: calculated value of the total pressure in the drying chamber at the instant k during said test, [Pa]pc,meas,k: measured total pressure in the drying chamber measured at the instant k during said test, [Pa]. 16. A method according to claim 10, wherein said time constant (t) of said freeze-drying process is calculated by the equation: τ=VcMwRpAs,tRTi,0(eq.20)where:Vc: volume of the drying chamber, [m3]Mw: molecular mass of the solvent, [kg mol−1]Rp: resistance of the dried layer to the vapour flow, [m s−1]As,t: total area of the interface of sublimation, [m2]R: ideal gas constant, [J K−1mol−1]Ti,0: temperature of the product at the interface of sublimation (z=0) at beginning of PRT, [K]. 17. A method according to claim 13, wherein said time constant (t) of said freeze-drying process is calculated by the equation: τ=VcMwRpAs,tRTi,0(eq.20)where:Vc: volume of the drying chamber, [m3]Mw: molecular mass of the solvent, [kg mol−1]Rp: resistance of the dried layer to the vapour flow, [m s−1]As,t: total area of the interface of sublimation, [m2]R: ideal gas constant, [J K−1mol−1]Ti,0: temperature of the product at the interface of sublimation (z=0) at beginning of PRT, [K]. 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). 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 (jw,0) of said product, a total pressure (pc,0) in said drying chamber and a partial pressure of said solvent (pw,c,0) in said drying chamber (step 1);estimating a temperature of said product at the interface of sublimation (Ti0) at the beginning of said test (step 2);calculating the vapour pressure of said solvent at the interface of sublimation (pw,i) (step 3);calculating a resistance of a dried layer of said product to the vapour flow of said solvent (Rp) (step 4);calculating a thickness of a frozen layer of said product (Lf) (step 5);calculating a coefficient of heat transfer (Kv) 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 (pc) in said drying chamber (step 8);determining a value of the product temperature at the interface of sublimation at the beginning of said test (Ti0) that best fits the calculated value of the total pressure in the drying chamber (pc) and the measured value of the total pressure in the drying chamber (pc,meas) (step 9); andcalculating 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 (jw,0) of said solvent at the beginning of said PRT is calculated by using the equation: jw,0=VcMwAs,tRTcⅆpw,cⅆtt=t0(eq.27)where:Vc: volume of the drying chamber, [m3]Mw: molecular mass of the solvent, [kg mol−1]pw,c: partial pressure of said solvent in the drying chamber, [Pa]As,t: total area of the interface of sublimation, [m2]R: ideal gas constant, [J K−1mol−1]Tc: temperature of the vapour in the drying chamber, [K]t: time, [s]. 21. A method according to claim 20, wherein said product to be freeze-dried comprises a plurality of solvents and a sublimation flux (jsolv,r,0) of each solvent at the beginning of said test is calculated by using the equation: jsolv,r,0=VcMsolv,rAS,tRTi,0ⅆpsolv,r,cⅆtt=t0(eq.31)where:jsolv,r,0: sublimation flux at the beginning of PRT, [kg s−1 m−2]Msolv,r: molecular mass of the r-th solvent, [kg mol−1]psolv,r,c: partial pressure of the r-th solvent in the drying chamber, [Pa]Vc: volume of the drying chamber, [m3]As,t: total area of the interface of sublimation, [m2]R: ideal gas constant, [J K−1mol−1]Ti,0: temperature of the product at the interface of sublimation (z=0) at the beginning of PRT, [K]t: time, [s]. 22. A method according to claim 2, comprising repeating at least steps 0 to 11 at preset intervals. 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 (jw,0) of said product, a total pressure (pc,0) in said drying chamber and a partial pressure of said solvent (pw,c,0) in said drying chamber (step 1);estimating a temperature of said product at the interface of sublimation (Ti0) at the beginning of said test (step 2);calculating the vapour pressure of said solvent at the interface of sublimation (pw,i) (step 3);calculating a resistance of a dried layer of said product to the vapour flow of said solvent (Rp) (step 4);calculating a thickness of a frozen layer of said product (Lf) (step 5);calculating a coefficient of heat transfer (Kv) 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 (pc) in said drying chamber (step 8);determining a value of the product temperature at the interface of sublimation at the beginning of said test (Ti0) that best fits the calculated value of the total pressure in the drying chamber (pc) and the measured value of the total pressure in the drying chamber (pc,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 (jw,0) of said product, a total pressure (pc,0) in said drying chamber and a partial pressure of said solvent (pw,c,0) in said drying chamber (step 1);estimating a temperature of said product at the interface of sublimation (Ti0) at the beginning of said test (step 2);calculating the vapour pressure of said solvent at the interface of sublimation (pw,i) (step 3);calculating a resistance of a dried layer of said product to the vapour flow of said solvent (Rp) (step 4);calculating a thickness of a frozen layer of said product (Lf) (step 5);calculating a coefficient of heat transfer (Kv) 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 (pc) in said drying chamber (step 8);determining a value of the product temperature at the interface of sublimation at the beginning of said test (Ti0) that best fits the calculated value of the total pressure in the drying chamber (pc) and the measured value of the total pressure in the drying chamber (pc,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.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.