Experimental Measurement of Freeze Drying Characteristics...
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The 21 st International Symposium on Transport Phenomena 2-5 November, 2010, Kaohsiung City, Taiwan Experimental Measurement of Freeze Drying Characteristics of Spray-Frozen Particles in a Tray and in a Vial Chi Sung Song 1* , Jae-Hyung Kim 1 and Jin Hyun Nam 2† 1 Energy Plant Division, Korea Institute of Machinery and Materials (KIMM), Daejeon 305-343, Korea 2 School of Automotive, Industrial, and Mechanical Engineering, Daegu University, Gyungsan 712-714, Korea * presenter † contact: [email protected] ABSTRACT In this study, freeze drying characteristics of spray- frozen particles were experimentally investigated using a prototype spray freeze dryer developed for inhalable drug production. To obtain uniformly frozen particles, an albumin solution (sample protein specimen) was sprayed directly into a pool of liquid nitrogen using a two-fluid nozzle installed on the spray freeze dryer. The freeze drying time for the microsized spray-frozen particles was then determined by measuring the product temperature contained in a tray, or the product mass in a vial. For tray freeze drying of the spray-frozen particles, drying time was estimated to be about 10 h, 15 h, and 22 h for the product height of 2 mm, 5 mm, and 7 mm, respectively, which showed a strong correlation between the product height and the drying time. In contrast, for vial freeze drying of the spray-frozen particles, drying times for the product height of 17 mm and 25 mm were measured to be relatively similar as about 21 h and 23 h. The shorter drying time obtained in the vial freeze drying experiments and its weaker dependency on the product height were discussed along with different heat transfer mechanisms for tray and vial freeze drying processes. INTRODUCTION Freeze drying is the most suitable drying technology for high-quality and heat-sensitive products encountered in the food and pharmaceutical industries. In freeze drying, products are first frozen to subzero temperatures (pre-freezing stage), and then the moisture in the products is removed by sublimation of ice (primary drying stage) and desorption of vapor (secondary drying stage). The direct transformation of ice to water vapor is achieved by maintain the freeze drying conditions below the triple point of water. Thus, freeze dried products can be preserved very long time in ambient conditions with less biological deterioration due to minimal residual water. In addition, they can be readily reconstituted to their initial state by adding water (Yu, 2004). Pulmonary drug delivery is currently attracting much research attention in the pharmaceutical fields for the non-invasive systemic administration of macromolecular drugs (insulin, proteins, and peptides), alternative to injection or oral administration. Inhalable drugs allow easy administration of powder medicine directly into the lungs by breathing, especially when timely medical treatment cannot be supported, e.g., on the war or an emergency (Shoyele, 2006). To efficiently penetrate deep into the human respiratory system and reach the alveolar region of the lung, pulmonary inhalable drugs should have adequate aerodynamic particle of around 1~5 μm diameters (Bosquillon et al., 2001). In addition, the geometric diameter should be also adequate around 10 μm for longer residence inside the lung. Spray freeze drying is a promising technology to produce such relatively large porous micro particles for inhalable drugs. In the spray freeze drying, the product solution is first sprayed into a pool of liquid nitrogen using an atomization nozzle to generate microsized frozen particles (spray freezing stage). Then, the conventional freeze drying process is performed to dehydrate the slurry of spray-frozen particles. In fact, spray freeze drying was found to produce highly porous microsized particles having ideal properties for pulmonary drug delivery (Maa et al., 1999); the geometric diameter of spray freeze dried particles were rather large as 5~20 μm while the aerodynamic diameter was small as about 1~5 μm. Freeze drying is an expensive process that requires high energy and long time, in spite of the high quality of the freeze dried products. The operating condition such as subzero temperature and vacuum pressure leads to a very low drying rate, or equally, a very long drying time. Especially, the spray-frozen particles experience much slower drying rates due to increased heat and mass transfer resistances from highly porous structure inside the particles. Thus, the freeze drying characteristics of spray-frozen particles were investigated in this study. A prototype spray freeze dryer for production of inhalable powder medicine was designed and manufactured. Then, the evolution of temperatures inside the spray-frozen particles in a tray was measured by varying the product height, from which the drying time was also estimated. In addition, the freeze drying of spray-frozen particles in a vial was also studied by weighing the product mass using a microbalance equipment. Then, a correlation between the product height and the freeze drying time was suggested. EXPERIMENTAL Specimen The chicken egg albumin was selected as a model protein product. The powder albumin purchased from Sigma-Aldrich was well dissolved in distilled water to obtain an albumin solution of 2% (w/w) concentration. The measured glass transition temperature for the albumin solution was around -13°C. In order to avoid the collapse failure (partial melting of a product during the freeze drying process), the operating temperature should be maintained below the glass transient temperature. Spray Freezing Dryer In this study, a prototype spray freeze dryer was developed by incorporating a spray freezing module into a commercial batch-type freeze dryer (model PVTFD30R, Ilshin Lab Co.) as shown in Fig.1. The system consists of a vacuum chamber with a pump and a compressor, a atomization system, a liquid nitrogen tray, a heating shelf, and connecting tubing. The atomization was performed with an air/liquid two-fluid nozzle. Silicon oil was used as the heat transfer fluid that circulates between the 196
Transcript of Experimental Measurement of Freeze Drying Characteristics...
The 21st International Symposium on Transport Phenomena 2-5 November, 2010, Kaohsiung City, Taiwan
Experimental Measurement of Freeze Drying Characteristics of Spray-Frozen Particles
in a Tray and in a Vial
Chi Sung Song1*, Jae-Hyung Kim1and Jin Hyun Nam2†
1 Energy Plant Division, Korea Institute of Machinery and Materials (KIMM), Daejeon 305-343, Korea 2 School of Automotive, Industrial, and Mechanical Engineering, Daegu University, Gyungsan 712-714, Korea
* presenter † contact: [email protected]
ABSTRACT In this study, freeze drying characteristics of spray-frozen particles were experimentally investigated using a prototype spray freeze dryer developed for inhalable drug production. To obtain uniformly frozen particles, an albumin solution (sample protein specimen) was sprayed directly into a pool of liquid nitrogen using a two-fluid nozzle installed on the spray freeze dryer. The freeze drying time for the microsized spray-frozen particles was then determined by measuring the product temperature contained in a tray, or the product mass in a vial. For tray freeze drying of the spray-frozen particles, drying time was estimated to be about 10 h, 15 h, and 22 h for the product height of 2 mm, 5 mm, and 7 mm, respectively, which showed a strong correlation between the product height and the drying time. In contrast, for vial freeze drying of the spray-frozen particles, drying times for the product height of 17 mm and 25 mm were measured to be relatively similar as about 21 h and 23 h. The shorter drying time obtained in the vial freeze drying experiments and its weaker dependency on the product height were discussed along with different heat transfer mechanisms for tray and vial freeze drying processes. INTRODUCTION Freeze drying is the most suitable drying technology for high-quality and heat-sensitive products encountered in the food and pharmaceutical industries. In freeze drying, products are first frozen to subzero temperatures (pre-freezing stage), and then the moisture in the products is removed by sublimation of ice (primary drying stage) and desorption of vapor (secondary drying stage). The direct transformation of ice to water vapor is achieved by maintain the freeze drying conditions below the triple point of water. Thus, freeze dried products can be preserved very long time in ambient conditions with less biological deterioration due to minimal residual water. In addition, they can be readily reconstituted to their initial state by adding water (Yu, 2004). Pulmonary drug delivery is currently attracting much research attention in the pharmaceutical fields for the non-invasive systemic administration of macromolecular drugs (insulin, proteins, and peptides), alternative to injection or oral administration. Inhalable drugs allow easy administration of powder medicine directly into the lungs by breathing, especially when timely medical treatment cannot be supported, e.g., on the war or an emergency (Shoyele, 2006). To efficiently penetrate deep into the human respiratory system and reach the alveolar region of the lung, pulmonary inhalable drugs should have adequate aerodynamic particle of around 1~5 μm diameters (Bosquillon et al., 2001). In addition, the geometric diameter should be also adequate around 10 μm for longer residence inside the lung. Spray freeze drying is a promising technology to produce such relatively large porous micro particles for
inhalable drugs. In the spray freeze drying, the product solution is first sprayed into a pool of liquid nitrogen using an atomization nozzle to generate microsized frozen particles (spray freezing stage). Then, the conventional freeze drying process is performed to dehydrate the slurry of spray-frozen particles. In fact, spray freeze drying was found to produce highly porous microsized particles having ideal properties for pulmonary drug delivery (Maa et al., 1999); the geometric diameter of spray freeze dried particles were rather large as 5~20 μm while the aerodynamic diameter was small as about 1~5 μm. Freeze drying is an expensive process that requires high energy and long time, in spite of the high quality of the freeze dried products. The operating condition such as subzero temperature and vacuum pressure leads to a very low drying rate, or equally, a very long drying time. Especially, the spray-frozen particles experience much slower drying rates due to increased heat and mass transfer resistances from highly porous structure inside the particles. Thus, the freeze drying characteristics of spray-frozen particles were investigated in this study. A prototype spray freeze dryer for production of inhalable powder medicine was designed and manufactured. Then, the evolution of temperatures inside the spray-frozen particles in a tray was measured by varying the product height, from which the drying time was also estimated. In addition, the freeze drying of spray-frozen particles in a vial was also studied by weighing the product mass using a microbalance equipment. Then, a correlation between the product height and the freeze drying time was suggested. EXPERIMENTAL Specimen
The chicken egg albumin was selected as a model protein product. The powder albumin purchased from Sigma-Aldrich was well dissolved in distilled water to obtain an albumin solution of 2% (w/w) concentration. The measured glass transition temperature for the albumin solution was around -13°C. In order to avoid the collapse failure (partial melting of a product during the freeze drying process), the operating temperature should be maintained below the glass transient temperature. Spray Freezing Dryer
In this study, a prototype spray freeze dryer was developed by incorporating a spray freezing module into a commercial batch-type freeze dryer (model PVTFD30R, Ilshin Lab Co.) as shown in Fig.1. The system consists of a vacuum chamber with a pump and a compressor, a atomization system, a liquid nitrogen tray, a heating shelf, and connecting tubing. The atomization was performed with an air/liquid two-fluid nozzle. Silicon oil was used as the heat transfer fluid that circulates between the
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refrigerator and the heating shelf. Thus, the operating condition was controlled by regulating the silicone oil temperature.
Procedure
The experiments were conducted according to the following procedures. First, liquid nitrogen is filled into the tray in the drying chamber. A pressurized air (about 1 bar, gauge pressure) and the prepared 2% albumin solution were supplied to the two-fluid nozzle. The flow rate of albumin solution was 25 ml/min, and the nozzle was placed 150 mm above the surface of liquid nitrogen. Then, microsized liquid droplets were sprayed into and frozen inside the liquid nitrogen tray. After the liquid
nitrogen was fully evaporated, the freeze drying process was conducted by controlling the silicone oil temperature at -22°C (below -13°C, glass transition temperature) and the vacuum pressure below 100 mTorr. See Table 1 for the experimental conditions. During the tray spray freeze drying experiments, the product temperatures at three different positions inside the tray (the center, middle, and outer radial locations) were measured. The experiments were continued for long time enough for the completion of the primary drying stage. On the other hand, the experimental procedure for the vial spray freeze drying was different. First, the albumin solution was atomized using the two-fluid nozzle system, similar to that shown in Fig. 1. However, a sampling equipment was used, as shown in Fig. 2, to collect the spray-frozen particles and dispense them into a vial for microbalance measurement. Once a vial was filled with a proper amount of spray-frozen particles, the freeze drying was performed as before. During the vial spray freeze drying experiment, the product mass was measured at a given interval using an microbalance (CWS-40, Christ) shown in Fig. 3. The microbalance could weigh 0.001~50 g sample in a vial at very low temperature environments up to -40°C, thus suitable for the freeze drying applications. RESULTS AND DISCUSSION
Albumin Microstructure Fig. 4 shows the scanning electron microscopy (SEM) images for the spray freeze dried particles obtained using the prototype spray freeze dryer. In Fig. 4, highly porous structures inside the spray freeze dried particles are clearly observed. These porous particles
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Figure 1. Schematic diagram of the prototype spray freeze dryer developed in this study.
Figure 2. Schematic diagram of the sampling system for collecting spray-frozen particles and dispensing them to a vial.
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Figure 3. Schematic diagram of feeding system of spray-frozen particles for a vial.
Table 1. Primary drying conditions.
Case Oil temp. Exp. time Prod. height Tray case 1 -21°C 25 h 3 mm case 2 -21°C 48 h 5 mm case 3 -21°C 48 h 7 mm Vial case 1 -21°C - 17 mm case 2 -21°C - 25 mm
Figure 4. SEM images of spray freeze dried particles.
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with large volumetric surface area are favorable for enhancing the bioavailability and solubility of drugs. Most of the spray freeze dried particles observed in Fig. 4 are about 20 μm in diameter, which is consistent with the droplet size generated from the two-fluid nozzle. A spray particle analyzer (Malvern Instruments) study showed that the Sauter mean diameter (SMD) was about 8 μm for the two-fluid nozzle atomization with an air pressure of 1 bar (gauge pressure). Therefore, the dimensional stability of the spray-frozen particles before and after the freeze drying process was high, which indicates the
particle size can be controlled by changing the droplet size. Spray Freeze Drying in a Tray The measured temperature histories for the freeze drying of spray-frozen particles in a tray are presented in Fig. 5. Three different product heights, i.e., H = 3 mm (case 1), 5 mm (case 2), and 7 mm (case 3), were studied experimentally. The product height in a tray was controlled by varying the amount of albumin solution sprayed into liquid nitrogen during the spray freezing stage. Note that, in this case, the product height, H, cannot be perfectly uniform in a tray, but can be varied along the radial position. Fig. 5(a) shows that product temperatures measured at the center, middle, and outer radial positions of the tray become rather constant after about 10 hours of freeze drying. During the primary drying stage, the product temperature becomes rather constant after sublimation of ice is completed. This is because the latent heat for ice sublimation is much larger than the sensible heat to increase the product temperature. Thus, the constant product temperature can be used as the indication for the completion of the primary drying stage. In Figs. 5(b) and (c), the primary drying time is estimated to be about 15 hours for case 2, and about 22 hours for case 3.
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Figure 5. Temperature evolution during the freeze drying of spray-frozen particles in a tray.
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Figure 7. Correlation for the primary drying time for the tray freeze drying.
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For more quantitative estimation of the completion of the primary drying stage, the rate of temperature change, a , was introduced:
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where T is the product temperature, t is the time, n is the present hour, and n-1 is the previous hour. In this study, the a smaller than 0.5°C/h was used as the criterion for reaching constant temperature and thus for completion of the primary drying. the evolution of a for the three tray spray freeze drying cases is shown in Fig. 6, where the estimated drying time is marked by arrows. Then, the relationship between the primary drying time and the product height in a tray is investigated in Fig. 7. It is observed that the primary drying time increases almost linearly according to the product height. This is because both the heat and mass transfer resistances increase proportional to the product height. A correlation was determined for the primary drying time, dryt , as:
)hour(30.3 972.0Htdry ´= . (2) Spray Freeze Drying in a Vial The freeze drying of spray-frozen particles in a tray was investigated by weighing the product mass during the process using a microbalance. The measured product mass is shown in Fig. 8, where the vial case 1 corresponds to the product height of 17 mm and the vial case 2 to the product height of 25 mm. The primary drying time is estimated to be about 21 h for the case 1 and about 23 h for the case 2, from the negligible mass changes after those times. Thus, different from the spray freeze drying in a tray, the primary drying time is rather insensitive to the product height for the vial spray freeze drying. In addition, the primary drying time is much shorter for the vial spray freeze drying compared with that for the tray spray freeze drying. One reason for the observed faster primary drying in a vial is related to the heat transfer rate. For the tray freeze drying, heat is mainly provided by conduction from
the heating shelf and by radiation from surrounding to the product (one-dimensional heat transfer). However, for the vial freeze drying, heat is also provided by radiation at the side wall of the vial. Thus, this multi-dimensional effect accelerates the heat transfer in the product, resulting in higher drying rates. In addition, the thermal properties of the tray and the vial were also different. CONCLUSION An experimental study was conducted to investigate the freeze drying behaviors of spray-frozen particles in a tray and in a vial. For the experiments, a prototype spray freeze dryer developed for the production of inhalable powder medicine was used. A 2% albumin solution was adopted a sample protein product. The freeze drying behaviors were studied by measuring the product temperature during the tray freeze drying experiments, or by weighing the product mass during the vial freeze drying experiments. A microbalance device was used for accurate weight measurement at subzero temperature and vacuum pressure environment. From the measured product temperature and weight, the primary drying time was estimated for different heights of spray-frozen particles in a tray and a vial.
(1) For the tray spray freeze drying, the primary drying time was about 9.6 h for H=3 mm, 15.7 h for H=5 mm, and 22.0 h for H= 7 mm.
(2) An almost linear correlation was determined for the primary drying time for the tray spray freeze drying, i.e., the drying time increased almost proportional to the product height.
(3) For the vial spray freeze drying, the primary drying time was found to rather insensitive to the product height. In addition, the drying rate was faster for the vial freeze drying than that for the tray freeze drying, which is due to the enhanced heat transfer through the side wall of the vial. NOMENCLATURE H product height, m T temperature, °C t time, h a rate of change in product temperature, °C/h REFERENCES Bosquillon, C., Lombry, C., Preat, V. and Vambever, R. (2001): “Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance”. Journal of Controlled Release, Vol. 70, pp. 329-339. Maa, Y.F., Nugyen, P.A., Sweeney, T., Shire, S.J. and Hsu, C.C. (1999): “Protein inhalation powders. Spray drying vs. spray freeze drying”. Pharmaceutical Research, Vol. 16, pp. 249-254. Shoyele, S.A. (2006): “Particle engineering techniques for inhaled biopharmaceuticals”. Advanced Drug Delivery Reviews, Vol. 58, pp. 1009-1029. Yu, Z. (2004): “Spray freezing into liquid nitrogen for highly stable protein nanostructured micro particles”. Europeon Journal of Pharmaceutics and Biopharmaceutics, Vol. 58, pp. 529-537.
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Figure 8. Weight change during the freeze drying of spray-frozen particles in a tray.
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