Fine Particle Pharmaceutical Manufacturing Using Dense Carbon

Chapter 21

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on February 21, 2018 | https://pubs.acs.org Publication Date: August 31, 2003 | doi: 10.1021/bk-2003-0860.ch021

Fine Particle Pharmaceutical Manufacturing Using Dense Carbon Dioxide Mixed with Aqueous or Alcoholic Solutions 1,*

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1

Edward T . S. Huang , Hung-yi Chang , C. D. Liang , and R . E. Sievers 1,3

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Center for Pharmaceutical Biotechnology, Department of Chemistry & Biochemistry, and CIRES, 214 UCB, University of Colorado, Boulder, C O 80309-0214 Chemical Engineering Department, National Cheng-Kung University, Taiwan Aktiv-Dry L L C , 655 Northstar Court, Boulder, C O 80304 2

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Abstract This paper describes a newly patented CAN-BD (Carbon dioxide Assisted Nebulization with a Bubble Dryer ) process, utilizing dense CO to micronize solutes to fine particles in a diameter range of 0.6 to 5 μm. The potential applications of this process are in thin film deposition, fine powder generation, and drug delivery. ®

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The fine particles are generated by (a) intimately mixing dense CO (at super- or sub-critical conditions) and a liquid solution (containing a dissolved solute of interest) in a small volume tee at about 83 bar and room temperature, (b) expanding this mixture through a 10 cm long capillary tube flow restrictor (with inner diameters of 50, 74 or 100 μm) into a drying chamber at atmospheric pressure to generate an aerosol, and (c) drying the aerosol plume with preheated air or nitrogen gas at temperatures between 10 and 65°C to form dry powders. Fine dry powders of disaccharide sugars, proteins, water-soluble and alcohol -soluble drugs have been generated with a lab CAN-BD unit (using a glass drying chamber with a volume of one to two liters) at a liquid flow rate of 0.3 to 2 mL/min. In a scaled up prototype unit (utilizing a 170-liter drying chamber with a thin stainless steel wall), aqueous solutions with 10% solute have successfully been nebulized and dried at a liquid flow rate of 20 mL/min. 2

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© 2003 American Chemical Society

Gopalan et al.; Supercritical Carbon Dioxide ACS Symposium Series; American Chemical Society: Washington, DC, 2003.

325 This paper presents experimental results of nebulizing aqueous solutions o f mannitol and myo-inositol utilizing a lab C A N - B D unit. The effect of certain operating parameters on particle characteristics has been investigated. The particle size (a) decreases with reduction in solute concentration, and (b) decreases with increase in the ratio of dense C 0 to aqueous solution flow rates.


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Supercritical Fluid Technology for Particle Generation A fluid is said to be in a supercritical state when it exists above its critical pressure ( P ) and critical temperature ( T ) . A supercritical fluid (SCF) exhibits significant solvent strength when it is compressed to liquid-like densities (1). On a plot of reduced density ( p = p/p ) vs. reduced pressure (PR = P/Pc) with reduced temperature ( T = T/Tc) as a parameter, the reduced fluid density can increase from gas-like density (-0.1) to liquid-like density (>2.0) within a reduced temperature range of 0.9-1.2, as the fluid is compressed beyond a reduced pressure greater than 1.0. Near the critical point, the slope of a constant temperature (T ) curve would be almost infinite, which implies that a slight change in pressure can cause a tremendous change in density. Since fluid density is closely related to fluid solvent power, a small change in pressure and temperature near the critical point can easily regulate the solvent power of a SCF. The most commonly used SCF is carbon dioxide. This fluid is a popular supercritical solvent, due to its inert nature as well as its mild critical conditions ( P of 73.8 bar and T of 31.1°C). c

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In the past two decades, a lot of work has been done on applications of SCF technology in the fields of extraction, materials and particle engineering (1,2). A brief review of fine particle generation processes using supercritical (SC) C 0 will be presented in the following. For detailed information, the readers are referred to literature articles (3, 4, 5). Particle generation processes can be classified as follows: 2

(A)

Solid-SCF system: Due to the significant solvent power of SC C 0 , this solvent can dissolve various intermediate and high molecular weight solutes. The process taking advantage of this property is called Rapid Expansion from Supersaturated Solution, RESS (6). It involves a binary solid-SC C 0 system, in which the solid to be micronized is dissolved in SC CO2 at a pressure greater than the P of C 0 (73.8 bar). This singlephase mixture is then expanded through a nozzle or a flow restrictor from a supercritical pressure to a low pressure. Pressure reduction causes C 0 to lose its solvent power, which results in precipitating solids as micron-size particles. Utilization of this process is limited because not many solids 2

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have high solubility in S C C 0 . Sometimes a co-solvent (e.g., alcohol) can be added to increase solubility, but such a method is not suited for water-soluble pharmaceuticals. 2

Soiid-SCF-Solvent system: The types o f particle generation in this category normally use S C C 0 as an anti-solvent. The other two components in the ternary system are a solvent and a solid (or solute). For this type o f S C F process to work, (a) the solvent needs to be "fully" miscible with the S C C 0 and (b) the solid needs to be soluble in the solvent but not significantly in C 0 . Since water is only partially miscible with C 0 (i.e., about 2 mole % C 0 in water at 100 bar), water cannot be used in this process. Several organic solvents (e.g., alcohol, acetone and D S M O , etc.) are fully or nearly fully miscible with S C C 0 and are used frequently in this application. Under supercritical conditions, S C C 0 is mixed with the liquid organic solution. Since SC C 0 , acts as an antisolvent, and is miscible with the organic solvent, it extracts and swells the solvent, and super-saturation of the solution results in crystallization (or precipitation) of solid. The types of S C F processes belonging to this category are, (a) G A S (gas Anti-Solvent) or S A S (Supercritical fluid AntiSolvent) (7, 8) (b) ASES (Aerosol Solvent Extraction System) (9,10) (c) P C A (Precipitation with Compressed fluid Anti-solvent) (11) (d) SEDS (Solution Enhanced Dispersion by Supercritical fluids) (12)


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One drawback of the anti-solvent processes is the requirement of the use of an organic solvent. This may lead to a problem of residual organic solvent left in the final dry powder product. Furthermore, some solutes are not stable in organic solvents. Another disadvantage is the requirement of high-pressure autoclaves, since anti-solvent crystallization must occur under supercritical conditions of C 0 . This requirement makes it difficult to use the process in scaled-up applications (13). In an attempt to extend applications of these processes to the water-soluble solids, it is necessary to achieve "full" miscibility between SC C 0 and the aqueous solution. This has been accomplished by adding an organic co-solvent (e.g., ethanol) to the system (14). Hence, the spray nozzle of the SEDS process was modified to handle three incoming streams, i.e., SC C 0 , a co-solvent, and an aqueous solution containing the solid of interest. However, this method also ends up with an organic solvent in the system, so the problems mentioned above still remain. 2

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327 There are other 3-component processes, i.e., PGSS (15) and C A N - B D (16, 17). PGSS stands for Particle Generation from Supercritical Solution. This process is similar in principle to RESS. The SC C 0 is dissolved in a molten solute or a liquid solution with suspensions of interest, and the resulting solution under high pressures is fed through a nozzle (or a flow restrictor) to effect a rapid expansion at ambient conditions. This process does not rely on the solubility of a solute in SC C 0 , but rather on the solubility of SC C 0 in a liquid solution. Lastly, the C A N - B D process to be described in the following is unique and differs from all the above processes described. In C A N - B D , dense C 0 and the liquid solution to be nebulized are intimately mixed in a small volume tee to form microbubbles and microdroplets. The amount of C 0 in this mixture, which facilitates aerosolization and drying as the aerosol plume is formed in a drying chamber, is more important than the solubility change requirement of all the supercritical fluid processes described above. 2


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Principle of the CAN-BD Process The C A N - B D process is a patented nebulization process (16,17). The experimental setup of the process has been described elsewhere ( 1 9 - 2 1 ) . A schematic of the C A N - B D apparatus is shown in Figure 1. The unique features of this process are (a) simultaneous micronizing and drying, (b) drying at low temperatures, 10 to 65°C, (c) no organic solvent required when nebulizing an aqueous solution, (d) no high-pressure autoclave required, and (e) a continuous process, which can easily be scaled-up. Solvents used in the C A N - B D process can be water, alcohol or water-alcohol mixtures, or other solvent with which C 0 is compatible. Solute concentrations typically vary from 0.1 to 10 % by weight. Liquid C 0 at room temperature is compressed with a syringe pump to a pressure above its critical pressure (e.g., 83 bar). A t a constant pressure (e.g., 83 bar), the dense C 0 and the liquid solution are intimately mixed in a small volume tee at sub or super-critical conditions of C 0 (e.g., near room temperature and 83 bar) to form an emulsion. The nebulization is usually effected with a liquid flow rate of 0.3 mL/min and a dense C 0 flow rate of 1 to 3 mL/min. The resulting emulsion is expanded through a -10 cm long capillary tube flow restrictor into a two-liter glass-drying chamber at atmospheric pressure to generate aerosols of microbubbles and microdroplets. This set of experiments utilized three restrictors with inner diameters of 50, 74, and 100 pm, subsequently larger diameter restrictors have been used with much larger drying chambers. 2

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Pre-heated air or nitrogen gas is passed through the drying chamber at 20 liters/min to provide heat for aerosol drying. The drying of the aerosols can be achieved with the drying chamber temperature maintained between 30 to 65°C i f


328 water is used as a solvent. If the solvent is alcohol, the drying can be achieved at temperatures much lower than 30°C. Finally, the dry powders are collected on a fdter membrane (with a pore size of 0.45 pm), which is attached to the bottom of the drying chamber. The process involves continuous flow o f a solution and dense C 0 through 1/16 inch O D stainless steel tubing to generate dry powder. (No high-pressure autoclave is required for the C A N - B D process). Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on February 21, 2018 | https://pubs.acs.org Publication Date: August 31, 2003 | doi: 10.1021/bk-2003-0860.ch021

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These are illustrative conditions and a wide variety of operating parameters have been tested. For example, lab-scale units have been used to generate fine powders of sugars (trehalose, lactose, sucrose), proteins (trypsinogen, lactate dehydrogenase, ovalbumin), water-soluble drugs (tobramycin sulfate, albuterol sulfate, and cromolyn sodium) and alcohol-soluble drugs (naproxen, amphotericin B , and budesonide) (19 - 26). For the C A N - B D treatment of the alcohol-soluble solutes, the drying temperature can be as low as 5°C, since alcohol with its higher vapor pressure is much easier to evaporate than water. In a scaled up prototype C A N - B D unit (utilizing a 170-liter drying chamber with a thin stainless steel wall), a 10% aqueous solution o f NaCI or mannitol has successfully been nebulized at a liquid solution flow rate of 20 mL/min (22).

Figure 1

A n experimental C A N - B D apparatus


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Materials and Analyses Mannitol (99%) was supplied by Pfanstiehl Lab (Waukegan, Illinois), myoinositol (99%) by Sigma. Carbon dioxide (99%) and nitrogen (99%) were supplied by A i r Gas. Samples of micronized powders were analyzed by a scanning electron microscope (ISI, model SX-30). The mean aerodynamic particle size distribution was measured using the Model 3225 Aerosizer DSP, which uses a laser time of flight principle.


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Results and Discussions In the C A N - B D process, the characteristics o f the powders generated (e.g., particle size and morphology, etc.) can be affected by the process operating parameters, i.e., drying temperature, C 0 pressure, solute concentration, flow rates of dense C 0 and aqueous solution, etc. Parametric studies were conducted to determine the particle characteristics that are most sensitive to process parameters. 2

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A . Parametric study using mannitol: The results of a parametric study conducted with aqueous solutions of mannitol are summarized in Table I. The base micronization test cases (Runs 1 and 2) were carried out using a 9.5 cm long flow restrictor with an inner diameter (ID) of 74 pm. The aqueous solution containing 10% mannitol was pumped to the mixing tee at a rate of 0.3 mL/min, while dense C 0 under a constant pressure of 83 bar was pumped into the second port of the mixing tee at a rate of about 2 mL/min. A preheated nitrogen gas stream was delivered into the drying chamber at 20 liters/min to maintain the temperature in the chamber at 50°C. 2

Runs 1 and 2 (Table I) were the base cases. The data show an average aerodynamic diameter of the particles to be 1.5 pm, with the diameters of 95% of the particles less than 3.5 pm, and the diameters of 5% of the particles less than 0.8 pm. Figure 2a shows the S E M image of the dry powders generated in Run 1. The remaining experiments were carried out by changing one parameter at a time from those in the base cases. When the drying temperature was varied, no significant change in particle size was observed between 85 and 50°C (Runs 3 and 1). The mean particle size increased to 2.08 pm when the temperature was lowered to 30°C (Run 4). This lower drying temperature probably caused the microbubbles and microdroplets to dry slower and have more opportunity to aggregate, so this could be the cause for the larger particle size. Yet this average particle size of 2 pm is still within



(%)

Cone

I.D. (μι»)

(Q

Temp Lig. (mL/min) 2

(mL/min)

co COrfiq.

10 10

10

10

Run 1

Run 4 74

74

74

74 74

1

0.2

Run 5

Run 6

10

10

1

Run 1

Run 8

Run 9

Effect of C(>2 flow rate Run 7 10

10

Run 1

100

100

74

50

74

74

74

Effect of sol ute concentration

10

Run 3

Effect of d rKing temperature

Run 1 Run 2

50

50

50

50

50

50

50

30

50

85

50 50

0.3

0.3

0.3

0.3

0.3

0.3

0.3

0.3

0.3

0.3

0.3 0.3

2.2

0.8

2.0

2.0

2.2

2.5

2.2

2.1

2.2 2.2

13.0

13.0

2

26.0

43.3

7.3

2.7

6.7

6.7

7.3

8.3

7.3

7.0

7.3 7.3

2

0.60

0.65

-

0.84

0.60

0.69

-

0.90

-

0.81

0.80 0.80

1.02

1.24

1.53

1.79

0.98

1.19

1.53

2.08

1.53

1.48

1.53 1.48

1.82

2.90

-

5.65

1.61

2.11

5.09

3.45

3.54 3.31

Particle size (um) >S% Ave. D 1

Fine Particle Pharmaceutical Manufacturing Using Dense Carbon

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