Solubility and Micronization of Griseofulvin in Subcritical Water

Ind. Eng. Chem. Res. 2010, 49, 3403–3410

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Solubility and Micronization of Griseofulvin in Subcritical Water Adam G. Carr, Raffaella Mammucari, and Neil R. Foster* Supercritical Fluids Research group, School of Chemical Engineering, The UniVersity of New South Wales, Sydney, New South Wales 2052, Australia

The technology developed in this work takes advantage of the temperature-sensitive dielectric constant of water to micronize hydrophobic compounds. At elevated temperatures subcritical water (SBCW) is a good solvent for nonpolar compounds, while at ordinary temperatures it behaves as an antisolvent. The solubility of the model compound griseofulvin in SBCW was determined at 70 bar and temperatures between 130 and 170 °C. In this work griseofulvin was dissolved in subcritical water. The resulting subcritical solution was then injected into water at room temperature to rapidly quench the temperature and trigger precipitation of the solute. The resulting particle morphology was markedly dependent on operating conditions such as temperature and concentration of the subcritical solution. It was possible to generate microparticles of griseofulvin with controllable morphologies. The process is rapid and does not involve the use of organic solvents. Introduction At temperatures above 100 °C intermolecular hydrogen bonding within water begins to lose strength, resulting in a reduction in polarity. At high temperatures the polarity of water is low enough for water to become equivalent to common organic solvents (Figure 1), which enables water to dissolve many hydrophobic compounds. Subcritical water has been used extensively as a solvent for hydrophobic organic compounds and in the separation of arrays of hydrophobic organic compounds from mixtures.1,2 Separation applications range from polycyclic aromatic hydrocarbons (PAHs) in soil1 to antioxidants in oregano.2 Mixtures of active pharmaceutical ingredients (APIs), such as phenacetin and methotrexate, have been separated by liquid chromatography using water as the eluent at temperatures up to 200 °C.4,5 All the tested APIs, with the exception of aspirin, were stable under the elevated temperatures used in the separations.4 Thus, it is possible to process a range of APIs in SBCW without altering their chemical structure. The concept of dissolving hydrophobic organic compounds in SBCW has been described in detail;6-9 however, the micronization of these compounds via a SBCW process is a novel concept. The production of micrometer-size particles via rapid precipitation from solutions has a number of benefits over the size reduction, or comminution, of pre-existing particles10 and can result in micronized products with narrow particle size distributions. Particularly effective techniques include spray drying and supercritical antisolvent precipitation (SAS).11 These methods rely on triggering the precipitation of a solute from a solvent via a significant change in the solvent dissolving power. The mechanism of precipitation differs from process to process and has been described in the literature.12-16 Control over particle morphology, heavy consumption of toxic solvents, and toxic residuals in the product are some of the drawbacks of conventional precipitation methods. The removal of trace solvents can be costly and time consuming yet essential, particularly for pharmaceutical products. The development of effective micronization processes free from organic solvents would be beneficial. Water is a nontoxic, ubiquitous, and * To whom correspondence should be addressed. Fax: +61 2 9385 5966. E-mail: [email protected].

Figure 1. Dielectric constant of water as a function of temperature. Each data point coincides with the saturated vapor pressure. The equivalent polarities of organic solvents at room conditions are listed along the curve. Data from the International Association for the Properties of Water and Steam substance (IAPWS).3

potentially universal solvent.6 A method using SBCW to micronize hydrophobic compounds is shown schematically in Figure 2. By mixing a SBCW solution with water at room temperature, a rapid temperature quench of the solution and a reduction in the polarity of the solvent results. The change in polarity can cause a supersaturation of the solution, which can lead to rapid precipitation of the solute. The yield of the precipitation process will be determined by the difference in solubility of the solute in SBCW and at room conditions. Published literature on SBCW lacks complete and accurate solubility data. The availability of solubility data is important for the construction of accurate solubility models and evaluation of promising technologies.17,18 The solubilities of PAHs in SBCW have been attained accurately by continuous extraction methods.7,19 Solutes were precipitated from saturated SBCW solutions in a cooling coil and then recovered in chloroform or hexane and analyzed by gas chromatography and mass spectrometry.7 Complete and accurate solubility models applicable to SBCW systems are yet to be developed. A number of attempts have been made:19-21 Miller et al. used a second-order fit of solubility as a function of temperature,19 Kara´sek et al. used a model based

10.1021/ie901189r  2010 American Chemical Society Published on Web 02/22/2010

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Figure 2. Schematic of the micronization process using subcritical water as a solvent for the compound to be micronized and water at ambient temperature as the antisolvent.

on pure component properties,20 and Fornari et al. used a modified universal functional activity coefficient (M-UNIFAC) group contribution model.21 The solubilities of 11 PAHs were predicted by M-UNIFAC and MF-UNIFAC models.21 The MF-UNIFAC model attained the highest accuracy through alteration of the aromatic carbon-water interaction parameters. The alteration reduced the average error of the M-UNIFAC model from 16.7% to 4.7%. However, the MF-UNIFAC model has not been tested for oxygenated organic compounds like the one studied in this work. The details of the models are not covered in this paper, as there are numerous papers dealing with the construction of the base model,22 the thermodynamic premise of the model,17,21 and updated interaction parameters.23,24 In this work, a batch system was used to measure the solubility of griseofulvin in SBCW and for the rapid precipitation of the API from SBCW solutions. The predicting ability of both the MF-UNIFAC and the M-UNIFAC models for the solubility of griseofulvin in SBCW was studied. Experimental Section Materials. Analytical-grade anthracene and griseofulvin (Penicillium griseofulVum), 95% purity, were purchased from Sigma-Aldrich. Reagent-grade acetone was from UNIVAR. HPLC-grade methanol was from Honeywell. Nitrogen grade 4.0 was purchased from Coregas. Deionized water was used for all experiments. Apparatus and Method. 1. Solubility Determination. A number of studies on the determination of solubilities in SBCW using dynamic (steady-state) systems have been reported.8,9,19,20 In this study, a new batch method was devised to determine the solubility of hydrophobic compounds in SBCW. A schematic of the experimental apparatus is shown in Figure 3. The fittings

and tubing were of stainless steel (type 316) from Swagelok. A Druck pressure transducer and indicator were fitted, and a Shimadzu GC-8A chromatography oven was used as the heating unit. The solubility vessel (SV) had an internal volume of 6.4 mL. At each end of the SV a threaded tube fitting was placed that held a 0.5 µm filter stone, which was used to retain undissolved particles in SV. For each run, the SV was loaded with an excess of griseofulvin (200 mg). The vessel was filled with water from the syringe pump P1. The “line end” was left open during the filling period, and once water dripped out, it was sealed off with a stainless steel cap. The water overflow ensured that air was purged from the system. The operating pressure was set to 70 bar via the syringe pump, thus ensuring that water was in the liquid state throughout the experiment.22 The system was allowed to equilibrate for 5 min with all valves closed prior to heating. The system was then brought to the selected temperature using the GC oven with pressure from thermal expansion relieved through V4. Once the set temperature was reached (which took 15-20 min depending on the final temperature) the system was left to equilibrate for 10 min while being internally stirred by an oscillating magnetic bar. The internal magnet was guided by an external iron ring magnet. Both the internal magnet and the iron ring magnet were purchased from AMF Magnetic. The ring magnet was attached to a stainless steel rod, which was guided out of a small hole in the oven. The rod was driven by an electric motor outside of the oven. The external ring magnet oscillated at 36 rpm, or 72 strokes/min. After 10 min mixing, the magnetic stirrer was stopped and the nitrogen supply, preset to 72 bar, was allowed to contact the solution via the opening of V3. High-pressure nitrogen maintained the constant vessel pressure, thereby preventing


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Figure 3. Schematic of the solubility apparatus.

vaporization of SBCW inside the apparatus during product collection. Valve V4 was opened slightly to permit the slow flow of SBCW solution into a capped vial. Once nitrogen started to flow into the collection vial, V4 was shut and the oven turned off. The presence of undissolved drug in the SV was observed after each experiment. The collection vial with the solution was then removed and weighed. Valve V3 was shut to isolate the nitrogen supply, and the system was depressurized through V4. After the system was cooled, the collection line was removed and subjected to a flow of 20 mL of reagent-grade acetone to collect deposited griseofulvin. Acetone solutions were collected in separate vials. The vial filled with acetone and the vial filled with water were dried for 24 h in air and in an oven at 50 °C, respectively. Both vials were then reweighed. In order to confirm that solvents were quantitatively removed, thermogravimetric analysis (TGA) was conducted (showing negligible solvent content). Each experiment was repeated a minimum of 4 times to ensure reproducibility. Solute quantification was by mass difference for samples above 1 mg; smaller samples were determined by UV spectrometry. Samples below 1 mg were produced between 100 to 150 °C for anthracene. The system was validated against the solubility of anthracene from the literature.19 In order to assess the stability of griseofulvin during processing, samples treated at temperatures above 200 °C were analyzed by FTIR spectroscopy using the KBr disk method. 2. Particle Formation. An apparatus for particle formation was designed from the apparatus used for the solubility study. A tee was added to permit flow to a collection vessel where precipitation occurred. The line to the precipitation vessel was 1/16” OD stainless steel tubing. The line was located inside the oven to minimize temperature changes prior to the particle formation vessel. A nozzle with an i.d. of 1/16” was used to deliver the SBCW solution into the particle formation vessel. The flow from the SV to the precipitation vessel was controlled by a valve. The precipitation vessel was set up according to the design shown in Figure 4. A backpressure of 20 bar was applied to the collection vessel to ensure that the water remained in the liquid state throughout the experiment and that the precipitation conditions were controlled. Lines downstream of the precipitation vessel were 1/8” o.d. stainless steel tubing.

A weighed amount of griseofulvin was loaded into the SV. The system was filled with water, and the pressure and temperature were equilibrated as described for solubility measurements. The system was then stirred for 10 min and subsequently contacted with nitrogen at 72 bar. The valve V3 was then cracked open 1/4 turn to allow the solution to flow to the sight gauge. The flow was stopped once the first nitrogen bubble was seen. The pressure of the sight gauge was continually monitored to ensure a constant backpressure was achieved. Each experiment was repeated a minimum of 3 times to ensure reproducibility. The suspension was collected from the sight gauge using a plastic syringe and transferred to a glass collection vial. The API was separated from the water suspension by vacuum filtration through a 0.45 µm HV hydrophilic Millipore membrane filter. The vacuum was provided by an Adixen Pascal 2000SD vacuum pump. Filtration generated a mostly dry product that was further dried by blowing air onto the product at room temperature for 10 min. (a) SEM and LS Methods. A Malvern Mastersizer S was used to determine the particle size of griseofulvin. Particle size and size distribution (PSD) analyses were carried out on the product taken directly from the particle formation vessel. Results are reported as volume mean diameter and size distribution. A Hitachi S900 SEM was used to image the product. The API powder was dispersed onto double-sided carbon tape and then placed on a sample holder. Samples were chromium coated. (b) XRD Method. The XRD machine used was a Philips multipurpose X-ray diffraction system (MPD). The griseofulvin powder was placed on a polished iron sample holder. The beam angle was varied from 6° to 60° with a 0.0206 2θ step size. The X-ray generator was set at 45 kV and 40 mA. The diffraction pattern of the processed materials was analyzed and compared to the diffraction pattern of the raw material and literature data to evaluate changes in the crystal structure. (c) DSC Method. A TA Instruments differential scanning calorimeter (DSC) 2010 was used. Dried powder samples (5-10 mg) were loaded into an aluminum pan and sealed. The samples were cooled to -50 °C, and the temperature was ramped at 10 °C/min to 300 °C in a nitrogen atmosphere. (d) Other Characterization Techniques. Fourier Transform Infrared (FTIR) spectroscopy was carried out to establish the

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Figure 4. Subcritical water particle formation apparatus.

Figure 6. Solubility of anthracene in SBCW; comparison of our work (]) to that of Miller et al. (9).19 Figure 5. FTIR spectra of raw griseofulvin and griseofulvin processed in SBCW at 200 °C.

Table 1. Griseofulvin Solubility in SBCW at 70 bar

chemical stability of griseofulvin. A Nicolet Impact 410 spectrometer was used for all experiments. The standard KBr method was used. Chemical stability was established by comparing the FTIR spectrum of the raw material griseofulvin to the processed griseofulvin. a

Results and Discussion 1. Stability/Solubility. The FTIR spectrum of griseofulvin was unchanged upon SBCW treatment as shown in Figure 5, thus indicating that the chemical structure of the compound was unchanged in SBCW conditions. A comparison between the solubility data of anthracene produced by our work and by Miller et al.19 is shown in Figure 6. The standard deviation of our experiments increased with

T (°C)

x2 (104) (mole fraction)

SD (104)

140 150 155 160 170

1.60 2.26 2.94 3.78 5.28 0.0061a

0.066 0.042 0.28 1.49 0.24

At 1 bar and 25 °C from ref 26.

temperature in a similar way to Miller et al. Overall, results from this work were within 12% of published values.19,20 The solubility data for griseofulvin in SBCW is shown in Table 1. A large solubility increase occurred between 160 and 170 °C, which is consistent with the trend exhibited for anthracene solubility in the literature.19 At elevated temperatures, nonpolar bonds between water and suitable side groups of the solutes can be formed.2


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Table 2. Subgroup Assignment for M-UNIFAC Interaction Parameters to Anthracene and Griseofulvina nb

subgroup

anthracene Vk

griseofulvin Vk

1 1 1 3 3 10 13 25

CH3 CH2 CH ArC ArCH CHO CH3O ACCl no. of subgroups ∆Hm (kJ/mol) Tm (K)

0 0 0 4 10 0 0 0 14 29 00021 49021

1 1 1 5 2 2 4 1 17 45 86027 49227

a Vk is the number of side groups present in the molecule. b n is defined as the nominal subgroup number from the original M-UNIFAC tables in ref 23.

Table 3. M-UNIFAC Models Errors in Predicting the Solubility of Griseofulvin and Anthracene in SBCW compound

M-UNIFAC

MF-UNIFAC

MF-Cl-UNIFAC

anthracene griseofulvin average

19% 42% 31%

9% 29% 19%

9% 4% 7%

Table 4. Precipitation Experiment Variables and Results

The solubility of griseofulvin in subcritical water at 170 °C was 2 orders of magnitude higher than that of anthracene. The higher solubility may be attributed to hydrogen bonding between water and the oxygenated side groups of griseofulvin. Kara´sek et al.9 suggested that the presence of oxygen within the solute molecules allows for the formation of hydrogen bonds between the solute and the water and that this is the reason for the relatively high solubility of oxygenated compounds. Hydrogen bonds within water molecules are progressively weakened with increasing temperature,25 and this may allow for the formation of hydrogen bonds between water and solute molecules. Thus, the solubility in SBCW is still expected to be higher for oxygenated compounds than for nonoxygenated compounds. 2. M-UNIFAC Solubility Models. The assignments of interaction parameter subgroups are shown in Table 2, where Vk is the number of subgroup k (where k is CH3, OH, etc.), ∆Hm is the enthalpy of melting, and Tm is the melting temperature. 3. M-UNIFAC Model. A comparison of the results obtained using the M-UNIFAC and MF-UNIFAC models are shown in Table 3. Errors were calculated using eq 1. The solubility curves generated by the two models are shown in Figure 7. AASD ) 100 ×

|

calcd ln(xobs ) 2 ) - ln(x2

ln(xobs 2 )

|

Figure 7. Solubility of griseofulvin in SBCW and predicted solubility values from the M-UNIFAC and MF-UNIFAC model. Interaction parameters are defined in Table 2.

temperature of SBCW concentration solution × 104(mole experiment (°C) fraction) Fa 1 2 3 4 5

140 160 170 170 170

a F ) Cobs/Ccalcd. scattering

1.6 2.9 5.3 2.7 1.8 b

1 1 1 0.5 0.25

product morphology

size (µm)

bipyramidal plate-agglomerates bipyramidal bipyramidal bipyramidal

20b 35b 15b 10-20 15

D50 ) volume average measured by light

(1)

To investigate the effect of side-group interactions on the accuracy of MF-UNIFAC, the chlorine interaction parameter was removed. The model generated accurate outputs: within 4% of the experimental data over the complete experimental temperature range. Further refinement of the M-UNIFAC model via the acquisition of solubility data for a range of organic compounds containing oxygen is recommended. Results (Particle Formation) 1. Effect of Temperature. The micronization of griseofulvin by SBCW processing has been conducted at various temperatures and concentrations of the subcritical solution; experimental conditions and results are summarized in Table 4. The particle size distributions (by volume) of griseofulvin crystals from experiments 1, 2, and 3 are shown in Figure 8. The particle size distributions were unimodal in all cases.

Figure 8. Particle size distribution of griseofulvin produced by SBCW micronization from saturated SBCW solutions at different temperatures.

Griseofulvin crystals have been produced by compressed fluid antisolvent (CFA) processes.28,29 CFA processes use a conventional solvent to dissolve the solute. Solute precipitation is triggered by contacting the solution with a compressed fluid antisolvent which expands and extracts the conventional solvent.14 Griseofulvin has been crystallized from acetone29 and chloroform28 by using carbon dioxide as the antisolvent. Precipitation is controlled by the diffusion of the supercritical fluid into the organic solvent (which decreases solute solubility) and the transfer of the organic solvent into the compressed fluid phase (which increases solute concentration). Thus, the fluid dynamic of the CFA process has a significant impact on the

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Table 5. Precipitation Methods for Crystalline Griseofulvin Microparticlesa method

conditions

CFA CFA CFA SBCWM SBCWM SBCWM

slow stirring-slow addition of antisolvent fast stirring-fast addition of antisolvent 35:1 griseofulvin:PSA 140 °C 160 °C 170 °C

dominant crystal morphology needle bipyramidal bipyramidal bipyramidal plate agglomerates bipyramidal

crystal length (µm)a

ref

1000 300 50 10 20 5

29 29 28 this work this work this work

a CFA, compressed fluid antisolvent process; PSA, poly sebacic anhydride; SBCWM, subcritical water micronization. from SEM images to be consistent between this article and literature data.28

b

Crystal length is determined

Figure 9. Griseofulvin precipitated in water at room temperature at 20 bar from saturated SBCW solutions at (a) 140, (b) 160, and (c) 170 °C.

morphology of the product. While our work may be governed by different mechanisms than CFA processes (such as the rate of heat transfer), the fluid dynamics of the injected solution will strongly affect the morphology of the precipitate. Thus, the CFA process and the SBCW process are compared based on the fluid dynamics of each method. Griseofulvin crystals are generally needle shaped. However, bipyramidal crystals were produced in experiments 1, 3, 4, and 5. Both morphologies correspond to a tetragonal crystal system and are the same polymorph.29 Bipyramidal crystals form when an even growth rate along all surfaces occurs, which in turn results from efficient mixing in the particle formation environment. Similar observations were made from compressed fluid antisolvent processes. A comparison between products from this work and from the compressed fluid antisolvent processes by De Gioannis et al.29 and Jarmer et al.28 are shown in Table 5. De Gioannis et al. investigated the effect of mixing procedure, while Jarmer et al. elaborated on the effect of an additive, poly sebacic anhydride (PSA), on griseofulvin morphology. De Gioannis et al. found that fast stirring and high fluxes of CO2 in the precipitation chamber resulted in bipyramidal crystals whereas low stirring rates and slow introduction of CO2 resulted in needle-like crystals. High stirring rates slowed down crystal growth in the preferred direction, resulting in an even growth rate on all crystal faces. High introduction rates of CO2 can generate faster supersaturation of the solution, thereby contributing to the formation of small particles. Thus, small bipyramidal crystals may be precipitated where homogeneous heat and mass transfer are achieved.29 Jarmer et al. found that a growth inhibitor was required to produce bipyramidal crystals of griseofulvin. It was suggested that the PSA selectively adhered to the fastest growing crystalline face of griseofulvin, thus equilibrating crystal growth in

all directions. It was thus shown that PSA acted as a crystal growth inhibitor, which prevented needle crystals from forming. The bipyramidal crystals produced by SBCW micronization may reflect a high degree of homogeneity throughout the particle formation stage. In particular, it may indicate efficient mass and heat transfer rates during the mixing of the SBCW solution stream with the water in the particle formation vessel. The particle size range produced is an indication of the high supersaturation achieved. In the SBCW micronization process, the level of supersaturation is determined by the difference in solubility at subcritical conditions and room conditions. Since the solubility of griseofulvin in subcritical water at 170 °C is almost double that at 140 °C, crystals from experiment 3 were produced with a degree of supersaturation double that of experiment 1. Figure 8 shows that particles from experiment 3 had a volume average particle size of almost one-half of the product from experiment 1. The effect of supersaturation level on particle size may have been enhanced by the larger temperature quench of experiment 3 (170 to 21 °C) compared to experiment 1 (140 to 21 °C). The corresponding faster heat removal may have triggered a more rapid precipitation. Particles formed at 160 °C, experiment 2, were about 10 µm in length with agglomerated plate-like morphology (Figure 9b). The peculiar morphology obtained from experiment 2 may be related to a discontinuity in water properties at 160 °C, where peculiar solute-water interactions take place. It has been documented that at 160 °C hydrogen-bonding cages that form around solute molecules in a water solution disappear.30 2. Effect of Concentration. In experiments 3, 4, and 5 the effect of supersaturation level at constant temperature was investigated. The micronization process was conducted at 170 °C at three different concentration levels: 100%, 50%, and 25% of the saturation concentration at 170 °C. Results are shown in Figure 10.


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Figure 10. Griseofulvin precipitated from SBCW solutions at 170 °C and different concentrations: (a) 5.3 × 10-4, (b) 2.6 × 10-4, and (c) 1.3 × 10-4 mol/mol.

Figure 11. X-ray diffraction of (a) bipyramidal crystals from SBCW processing, (b) needle-like crystals from SBCW processing, and (c) raw griseofulvin.

Experiments 4 and 5 generated crystals with a elongated dimension, which is an indication of a limited heat and mass transfer rate. It is possible that the lower saturation levels used in experiments 4 and 5 corresponded to the growth of a reduced number of crystallization nuclei. The crystallization process is generally slower for low supersaturation levels, and thus, mass and heat transfer are more likely to limit the process.31 Particles from experiment 5 were hollow (Figure 10c). The lack of griseofulvin deposition in the inner part of the crystal may indicate insufficient mass and heat transfer in the narrow channels within the structure of the forming crystals. X-ray diffraction and DSC performed on SBCW-produced griseofulvin crystals and on the raw material results are reported in Figures 11 and 12, respectively. Results indicate that all the morphologies produced by SBCW processing and the raw material were the same polymorphic form of the API. The XRD of griseofulvin samples from experiment 2 (needlelike morphology) exhibited peculiarities. The peaks at 13° and 26° were more intense than in the other samples, while the peak at 14° was less intense (Figure 11). Irregularities in the crystal structure may be the reason for the peculiarities in the XRD profile, as the changes appear reasonably small. The irregularities did not affect the thermal profile of any of the products, as

Figure 12. DSC diagrams for griseofulvin crystals: (a) bipyramidal crystals from SBCW processing, (b) needle-like crystals from SBCW processing, and (c) raw griseofulvin.

shown in Figure 12, thus confirming that the irregularities have a negligible effect on the crystal lattice bond strength. Conclusions The solubility of griseofulvin in SBCW water has been measured between 140 and 170 °C. A corrected MF-UNIFAC model was constructed with an average accuracy of 4% over the temperatures tested. Griseofulvin has been successfully precipitated from SBCW solutions with unimodal particle size distributions and uniform morphologies. Griseofulvin was stable upon SBCW treatment, and the products of SBCW micronization had a smaller particle size than griseofulvin micronized by other advanced techniques, such as compressed fluid antisolvent precipitation. The morphology of SBCW-produced samples could be manipulated by varying the operating conditions, mostly the supersaturation level in the particle formation stage. The process developed in this work is a step forward in the micronization of hydrophobic compounds as it eliminates the requirement of organic solvents and related postprocessing purification stages. The elimination of toxic processing media is advantageous for many applications, particularly in the biomedical and pharmaceutical sectors, where stringent regulations apply. Further work on an array of APIs is underway. The study of additional systems can contribute to a fundamental understanding of SBCW-solute interactions and can help

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ReceiVed for reView July 26, 2009 ReVised manuscript receiVed January 28, 2010 Accepted February 9, 2010 IE901189R

Solubility and Micronization of Griseofulvin in Subcritical Water

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