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Continuous Spherical Crystallization of Albuterol Sulfate with Solvent Recycle System Kohei Tahara, Marcus O'Mahony, and Allan S. Myerson Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b01159 • Publication Date (Web): 09 Sep 2015 Downloaded from http://pubs.acs.org on September 15, 2015
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Continuous Spherical Crystallization of Albuterol Sulfate with Solvent Recycle System Kohei Tahara1,2, Marcus O'Mahony1, Allan S. Myerson1,* 1
Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts
Avenue, 66-568, Cambridge, Massachusetts 02139, United States 2
Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-
Nishi, Gifu 501-1196, Japan KEYWORDS. Continuous spherical crystallization, MSMPR, Antisolvent crystallization, Solvent recycling, Albuterol
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ABSTRACT
Spherical crystallization enables the direct preparation of crystal agglomerates of active pharmaceutical ingredients (APIs) with improved crystal handling properties. The continuous spherical crystallization of albuterol sulfate as a model API was developed using a mixedsuspension, mixed-product removal (MSMPR) crystallizer. The application of a solvent recycling system for reuse of the antisolvent in the single-stage MSMPR crystallizer was also demonstrated. Spherical agglomerates of albuterol sulfate were obtained via antisolvent crystallization using the MSMPR crystallizer with water as the solvent and an ethyl acetate/emulsifier (Pluronic L-121) mixture as the antisolvent. Steady-state continuous spherical crystallization was rapidly achieved after 30 min, and a yield of >95% was obtained. The influence of process parameters such as the solvent/antisolvent ratio, emulsifier concentration, residence time, and reactor scale on the properties of the agglomerates formed during the crystallization process was examined. In the MSMPR crystallizer, the desired solvent to antisolvent ratio was maintained by controlling the flow rates of the feed, antisolvent, and recycle stream, and 90% of the mother liquor was recycled during the continuous spherical crystallization of albuterol sulfate by optimizing the rate of each stream.
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INTRODUCTION Crystallization is an essential separation and purification process in the pharmaceutical industry because the majority of active pharmaceutical ingredients (APIs) are produced in solid form1. The crystallization process can influence the performance of downstream operations such as filtration, drying, milling, powder mixing, and tableting2. Furthermore, physicochemical properties of the final product, such as dissolution rate also depend on the crystal morphology3 . The manufacture solid dosage forms such as tablets and capsules with appropriate powder handling properties of APIs is important. Poor flowability and handling properties make downstream processing of pharmaceutical powders such as direct tablet-compression or capsulefilling very difficult. Kawashima et al. developed the spherical crystallization method to increase the size of crystals through agglomeration and defined it as an agglomeration process that directly transforms crystals into compact spherical forms during the crystallization process4. The spherical crystallization technique has the potential to reduce the cost and labor associated with pharmaceutical production because a separate granulation process can be avoided. However, in order to control the quality of products manufactured via the use of simultaneous crystallization and agglomeration processes leading to particle granulation, extensive research and development is typically required 5. The optimization of solvents, excipients, and process parameters must be performed for each API and specific property desired. Continuous manufacturing has long been used to produce a wide variety of commodity chemicals in a highly cost-effective and reproducible manner. Recently, the pharmaceutical industry, which still largely utilizes batch processes, has paid greater attention to continuous
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manufacturing6, 7. Three main types of continuous crystallizers are employed for pharmaceutical manufacturing: mixed-suspension, mixed-product removal (MSMPR) crystallizers, plug-flow reactors (PFRs), and oscillatory baffled crystallizers (OBCs)8. PFRs generate small crystals with narrow size distributions9, 10. However, high flow rates and long tube lengths are necessary to achieve the required residence times, and clogging of the tube is often an issue. OBCs are also tubular crystallizers equipped with periodically spaced orifice baffles with oscillatory motion overlapped on the net flow11. MSMPR crystallizers are the most general crystallizers for continuous crystallization12, 13; thus, converting existing batch processes to continuous preparation using MSMPR crystallizers appears to be easier than using other crystallizers. We have developed a method for continuous spherical crystallization with a single-stage MSMPR system to overcome the main disadvantage of the conventional spherical crystallization technique, namely, the need for very large volumes of antisolvent. Herein we describe the application of the quasi-emulsion solvent diffusion (QESD) method, a typical spherical crystallization technique, to an MSMPR crystallizer. QESD was first used in 1989 by Kawashima and coworkers14. In this method, interactions between API and the solvent are stronger than those between the solvent and antisolvent solvents. The API is dissolved in solvent and when the solution is dispersed into the antisolvent, transient-emulsion (quasi-emulsion) droplets are produced, even though they are miscible. The transient emulsion is unstable due to increasing interfacial tensions between solvent and antisolvent. The solvent gradually diffuses outside emulsion droplets, and the antisolvent diffuses into droplets, which reduces the solubility of API inside the droplets and eventually causes API crystallization. Albuterol sulfate, which has previously been prepared as spherical agglomerates via batch-wise QESD by Nocent et al.15, was used as a model API. The mechanism is illustrated in Figure 1.
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Figure 1. Mechanism for spherical crystallization of albuterol sulfate via the quasi-emulsion solvent diffusion method.
The solvent and antisolvent were water and ethyl acetate containing an emulsifier (surfactant), respectively. The authors also reported that the solvent/antisolvent ratio (Ra) is an important parameter for the fabrication of spherical particles and should be less than 0.01, requiring the need for a large quantity of organic solvent (ethyl acetate) which is particularly relevant to the process being employed on an industrial scale. The use of organic solvents for industrial-scale production poses several issues, including the handling of disposal of hazardous substances, environmental pollution, and high costs16. Therefore, the feasibility of using an MSMPR crystallizer with a solvent recycling system for continuous spherical crystallization as a green chemistry approach for spherical crystallization was also demonstrated.
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EXPERIMENTAL SECTION 2.1. Materials Albuterol sulfate, (RS)-1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol sulfate, and Pluronic L-121, which is poly(ethylene glycol)-block-poly(propylene glycol)-blockpoly(ethylene glycol) (average Mn of approximately 4,400), were purchased from Sigma-Aldrich (Saint Louis, MO). Ethyl acetate was purchased from VWR international (Edison, NJ). All other chemicals were commercial products of ACS reagent grade.
2.2 Quasi-emulsion solvent diffusion method for albuterol sulfate In the antisolvent crystallization of albuterol sulfate, ethyl acetate was used as the antisolvent and water as the solvent. An aqueous solution of albuterol sulfate (0.3 mL, 0.25 g/mL) was mixed into ethyl acetate (50 mL) containing a surfactant as an emulsifier, and the mixture was stirred at 5°C using a magnetic stirring bar. After mixing for 30 min, the precipitated agglomerates were collected via filtration through a PTFE membrane filter (5-um pore size, Pall Life Sciences, Port Washington, NJ). The solid particles after filtration were washed with pure ethyl acetate, dried in an oven at 30°C for 24 h, and then stored in a desiccator.
2.3. Continuous spherical crystallization in an MSMPR crystallizer Figure 2 shows the schematic configuration of the MSMPR system for antisolvent spherical crystallization, and Table 1 lists the experimental parameters for all of the MSMPR studies.
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Figure 2. Schematic diagram of the single-stage MSMPR with solvent recycling.
Table 1. Experimental conditions for continuous spherical crystallization of albuterol sulfate using MSMPR. Solvent recylce
No solvent recycle
50%
90%
Exp. 1
Exp. 2
Exp. 3
Exp. 4
Exp. 5
Exp. 6
Exp. 7
Exp. 8
Water/antisolvent volume ratio
0.006
0.01
0.006
0.006
0.006
0.006
0.006
0.006
% Pluronic L-121 in antisolvent
4
4
2
4
4
4
4
4
Residence time (min)
30
30
30
60
30
30
30
30
Antisolvent volume (mL)
50
50
50
50
50
120
50
250
Overhead mechanical stirring (rpm)
600
600
600
600
600
600
600
600
Magnetic stirring bar
ー
ー
ー
ー
+
+
+
+
Flow rate of feed stream (mL/min)
0.010
0.017
0.005
0.010
0.010
0.024
0.005
0.005
Flow rate of recycle stream (mL/min)
ー
ー
ー
ー
ー
ー
0.84
7.55
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The system consisted of glass-jacketed crystallizers of different sizes (Ace Glass, Vineland, NJ), each with an overhead mechanical stirrer and independent temperature control, a filter unit with a medium glass fritted disk (Chemglass, Vineland, NJ), a separator (three-neck 250-mL flask), and four peristaltic pumps (Masterflex, Cole Parmer, Vernon Hills, IL) fitted with ChemDurance Bio tubing (Cole Parmer). During each MSMPR experiment, fresh albuterol sulfate in water (0.25 g/mL, room temperature) was continuously pumped into the crystallizer. The working volumes of the crystallizer were 50 mL, 120 mL, and 250 mL with a residence time of 30 or 60 min. Once crystallized, the suspension of albuterol sulfate crystals was removed and separated using the filter unit, and the albuterol sulfate crystals were collected from the filter unit. After filtration, the mother liquor was collected in the separator, and the solution was distributed to the waste stream or back to the crystallizer via the recycle stream according to the desired recycle ratio, which was defined as the ratio of the volumetric flow rate of the recycle stream to that of the feed stream. The semidried cake of albuterol sulfate crystal entrapped in the filter unit was washed with pure ethyl acetate, further dried in an oven at 30°C for 24 h, and then stored in a desiccator.
2.4. MSMPR crystallizer with a solvent recycling system The design of the solvent recycling system used with the MSMPR crystallizer was based on the desire to achieve the required solvent (water) to antisolvent (ethyl acetate) ratio inside the singlestage MSMPR crystallizer and maintain a steady state17. The flow rates for the feed, antisolvent, and recycle streams were calculated using mass balance equations to synchronize and maintain the desired operating conditions inside the crystallizer. At each residence time, the albuterol
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sulfate concentrations at the crystallizer outlet and in the recycle stream and the quantity of crystals collected on the filter unit were determined using high-performance liquid chromatography (HPLC).
2.5. Analyses and measurements The crystal size distribution and total count per second in the crystallizer were monitored online using focused beam reflectance measurement (FBRM, Lasentec, Mettler Toledo, Columbus, OH) technology. The Lasentec S400 probe measured the chord length distribution in situ. The concentration of the mother liquor and the albuterol sulfate content in the spherical crystals were determined using HPLC. Mother liquor samples were collected using PTFE syringe filters with a 0.2-µm pore size. An HPLC instrument (1100 Series, Agilent Technologies, Santa Clara, CA) with a ZORBAX Eclipse XDB-CN column (4.6 × 250 mm, 5 µm, Agilent Technology) was employed for determining the concentration at 276 nm using a UV detector (flow rate: 2.0 mL/min; injection volume: 10 µL). The shape of the crystals was observed via optical microscopy (Eclipse ME600, Nikon, Tokyo, Japan) and electron scanning microscopy (SEM, 6010LA, JEOL, Tokyo, Japan). The particle size distribution was determined using a laser diffraction instrument (Mastersizer 2000, Malvern instruments, Malvern, UK), for which isooctane was used as the albuterol sulfate dispersion medium. X-ray powder diffraction (XRPD) was performed using a PANalytical X’Pert PRO diffractometer. Sample was placed on a silicon zero background disk holder scanning from 5 to 40° using Cu Kα radiation source (1.5418 Å).
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RESULTS Spherical crystallization of albuterol sulfate using the quasi-emulsion solvent diffusion method The chemical structure and an SEM image of albuterol sulfate (commercially available (RS)-4[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol) are shown in Figure 3a and b.
Figure 3. (a) Chemical structure of albuterol sulfate. (b) SEM images of the starting commercial material.
As shown in Figure 3b, the albuterol sulfate crystals adopted a plate-like shape, which generally leads to poor powder handling properties, such as flowability, compaction, etc. The procedure for spherical crystallization of the albuterol sulfate was performed according to that reported by Nocent et al15. Water was used as the API solvent, and ethyl acetate with an added emulsifier was used as the antisolvent. The authors showed that the solvent/antisolvent ratio, or the so-
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called Ra parameter, influences the formation of albuterol sulfate spherical particles and should be
