Quasi-Emulsion Precipitation of Pharmaceuticals. 1. Conditions for Formation and Crystal Nucleation and Growth Behavior Xing
Wang,#
Jason M. Gillian, and Donald J. Kirwan*
Department of Chemical Engineering, UniVersity of Virginia, P.O. Box 400741, CharlottesVille, Virginia 22904-4741
CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 10 2214-2227
ReceiVed June 29, 2005; ReVised Manuscript ReceiVed May 31, 2006
ABSTRACT: Induction time and crystal morphology changed with agitation during the precipitation of salicylic acid in viscous, aqueous low molecular weight poly(ethylene glycol) 300 (PEG300) solutions with water as the antisolvent. Further, if antisolvent precipitations of either salicylic acid or methylparaben in aqueous PEG300 were conducted by equal volume mixing in a confined impinging jet, the exiting solution was optically clear and exhibited induction times as long as days. Significant mechanical agitation or seeding of the solutions induced rapid crystallization. Light scattering and particle size analysis supported the idea that a quasiemulsion was formed consisting of well-dispersed, solute-stabilized droplets (diameters of 100-1000 nm) of the viscous solution in the less viscous antisolvent. In agreement with Taylor’s droplet breakup theory, when a viscous fluid is added to a less viscous one, a quasi-emulsion can form if the viscosity ratio is above ∼3 and if a precipitatable solute is present. Induction time in these systems was a function of supersaturation ratio and mixing conditions. Generally, nucleation and growth occur on the outside of the droplets, but growth can occur within the droplets producing spherical crystals. Applications of quasi-emulsion precipitation (QEP) include polymorph control and chiral isomer separations from racemic conglomerates. Introduction Precipitation is widely used for particle formation, purification and separation in the pharmaceutical industry. Precipitation typically involves mixing two liquid streams to create supersaturation, which is the driving force for solutes to form crystals. Specifically, antisolvent precipitation involves mixing a solutecontaining solvent with a miscible liquid (antisolvent) in which the solubility of the solute is much lower. The volumes of the two streams to be mixed typically are comparable. During our study of the use of the environmentally benign, but viscous, solvent poly(ethylene glycol) 300 (PEG300) for antisolvent precipitation processes, it was found that, under certain conditions, the nucleation induction time exhibited unusual trends with agitation speed in a stirred tank as well as with jet velocity when using a confined-impinging-jet (CIJ) device to mix fluids.1 This behavior was not observed using a nonviscous solvent such as methanol. As described below, theoretical considerations and experimental observations led to the hypothesis that consistent microscale segregation existed in the “mixed” solution and caused these unusual observations. The origin of this phenomenon relates to the difficulty of mixing viscous and nonviscous fluids rapidly. This persistent microscale segregation is termed a “quasi-emulsion” in that, although the liquids are miscible, the solutions are only well-dispersed into each other and not homogeneously (molecularly) mixed. A quasi-emulsion precipitation mechanism is proposed and tested to define the conditions necessary to form quasi-emulsions and their subsequent effects on crystal nucleation and growth processes. In a companion paper in this issue, we will demonstrate one important application of the quasi-emulsion precipitation phenomena, namely, the control of polymorph formation during antisolvent precipitation.2
Figure 1. Chemical structures of solutes. solutes with various solvent/antisolvent combinations. The majority of the work used aqueous PEG300 solutions as the solvent and deionized water as the antisolvent. 1. Materials. Model solutes included the following. salicylic free acid (HS) methylparaben (MP) butylparaben (BP) glycine
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Their chemical structures are shown in Figure 1. The original solute studied was salicylic acid. We then expanded the study to other similar solutes to test whether the surfactant properties of the solute affected the phenomena observed. Finally, glycine, a watersoluble as opposed to PEG-soluble solute, was used to test the influence of the solute being dissolved in a nonviscous solvent. Solvents used included the following. methyl alcohol (MeOH) ethanol (EtOH) 1-propanol alcohol (1-PrOH) poly(ethylene glycol) 300 (PEG300)
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Chemicals used for mixing time characterization via the Bourne reaction included the following.
Experimental Section This study involved a characterization of mixing of viscous and less viscous fluids and then precipitation studies using a number of model * To whom correspondence should be addressed. E-mail: djk@ virginia.edu. # Present address: Crystallization Technology Laboratory, Research API, Pfizer Global R&D, 2800 Plymouth Road, Bldg 520-G346B, Ann Arbor, MI 48105.
2,2-dimethoxypropane (DMP) hydrochloric acid (HCl) sodium hydroxide (NaOH) sodium chloride (NaCl) ethyl alcohol (EtOH) poly(ethylene glycol) 15000-20000 (PEG20000) poly(ethylene glycol) 300 (PEG300)
10.1021/cg0503043 CCC: $33.50 © 2006 American Chemical Society Published on Web 08/29/2006
Aldrich (98%) Fisher (1 N) Fisher (1 N) Fisher (ACS reagent) Aldrich (HPLC grade) Aldrich Aldrich
Quasi-Emulsion Precipitation of Pharmaceuticals
Crystal Growth & Design, Vol. 6, No. 10, 2006 2215
Figure 4. Confined-impinging-jet mixer (from ref 4).
Figure 2. Batch stirred tank with laser detector and particle counter.
Figure 3. HS nucleation induction time detection (L > 1.62 µm). 2. Equipment and Procedures. Batch Stirred Tank and Induction Time Measurements. The equipment setup is shown in Figure 2. All solutions were filtered with a 0.2 µm membrane before using. The proper amount of solute was dissolved into the solvent. About 60 mL of solution was added into a 250 mL jacketed beaker with a Corning PC-410 stirrer plate and magnetic stir bar (10 × 24 mm) and maintained at 25 °C with a water bath. The appropriate amount of antisolvent was then added quickly by syringe into the beaker. The solution (slurry) in the beaker was then circulated (Masterflex 7524-50) through a laser particle sensor/counter (Pacific Scientific Instruments, HRLD 150JA and HIAC Royco 8000A) which detected particles in the range of 1.2150 µm with a maximum concentration of 18 000 particles/mL. In those cases in which constant counts were expected, circulation and counting continued (typically, a few milliliters passed through the sensor) until stable counts were obtained indicating that a representative sample was being measured. The data were stored on a computer for subsequent analysis. An example of nucleation detection by following the particle size distribution is shown in Figure 3. [The particle number density, n, is defined as ∆N(L)/∆L where N(L) is the total number of particles/mL smaller than a size L.] In this example, the induction time would be taken as 294 s, corresponding to the time when the particle count suddenly rose in the smallest size channel. The curve shown for t < 294 was essentially stable for all times up to 294 s. Crystals are analyzed with a Bausch & Lomb Balplan microscope.
Confined-Impinging-Jet. The CIJ mixer (Figure 4) was developed and extensively characterized by Johnson and Prud’homme3 for use in mixing approximately equal fluid volumes. The device used in this studied was graciously provided by Brian Johnson of Merck & Co., Inc., and complete details can be found in ref 3. Its mixing characteristics were further characterized by Gillian in his recent M.S. thesis.4 The jet diameters were 0.5 mm, and the exit diameter was 1.0 mm. The mixing chamber diameter was 2.3 mm, and it was 4.5 mm long. Mixing with the CIJ mixer is driven by a syringe pump (PHD2000, Harvard Apparatus) with two 60 mL syringes with flow rates up to 60 mL/min for each syringe [ujet ) 5.1 m/s]. The mixed solution was collected in a beaker or quartz cuvette for further analysis. A Tyndall effect (light scattering) of the mixed solutions in a cuvette was observed by shining a He-Ne laser (λ ) 633 nm) through it. Dynamic light scattering test of some mixed samples was performed with a Photocor Complex dynamic light scattering system (Photocor Instruments). Mixing Time Characterization. Although the mixing characteristics of the CIJ were characterized for mixing fluids of equal viscosity by Johnson and Prud’homme3 and Gillian,4 we tested its capabilities for mixing fluids of different viscosity. Competitive parallel chemical reactions, first proposed by Paul & Treybal5 and developed extensively by Bourne and co-workers6,7 and others,8 are used to measure the liquid-liquid mixing time in the device. The basic idea is to apply two competitive parallel chemical reactions with well-defined reaction constants in the mixing process so that one is extremely fast and the other one is slow. If the mixing is fast enough, the fast reaction will finish before the slow one can begin, and the characteristic chemical reactant for the slow reaction will not be consumed. On the contrary, if the mixing is slow (comparable to the reaction time for the second reaction), the characteristic chemical compound for the slow reaction will be consumed. Therefore, on the basis of the observed selectivity of the reaction set, a characteristic mixing time can be estimated. We followed the procedures of Johnson and Prudhomme3 and Gillian4 and utilized the rapid neutralization of NaOH (A) by HCl (B) in parallel with the slow acid-catalyzed hydrolysis of dimethoxypropane (D) to form methanol and acetone products as shown in eq 1. k1
A + B 98 P k2
D + B 98 Q + P + B
(1)
k2 , k1 The fast reaction is essentially instantaneous relative to the mixing, while the slow reaction has a characteristic time constant
tR ) 1/k2CD0
(2)
where CD0 is the initial concentration of DMP if completely mixed. Change of the value of CD0 allows changes in the value of the reaction time constant to probe the mixing time. The rate constant k2 for the acid catalysis of DMP is given by Baldyga et al.9 as a function of temperature and NaCl concentration. At room-temperature, tR can range from a lower limit of 5 ms at CD0 ) 300 mM due to solubility
2216 Crystal Growth & Design, Vol. 6, No. 10, 2006
Wang et al.
Figure 5. HS nucleation induction times in stirred beaker. Fast addition. S ) 1.5. Table 1. HS Induction Times in CIJ-Mixed Solutionsa CIJ volume velocity of one syringe, mL/min (jet velocity, m/s) supersaturation
10 (0.8)
20 (1.6)
30 (2.5)
40 (3.4)
50 (4.2)
S ) 1.6 S ) 3.5 S)5
instantly instantly
