Solubility, Solubility Modeling, and Precipitation of Naproxen from

Ind. Eng. Chem. Res. 2010, 49, 9385–9393

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Solubility, Solubility Modeling, and Precipitation of Naproxen from Subcritical Water Solutions Adam G. Carr, Raffaella Mammucari, and Neil R. Foster* Supercritical Fluids Research Group, School of Chemical Sciences and Engineering, The UniVersity of New South Wales, Sydney, New South Wales 2052, Australia

In this paper, the solubility of naproxen in subcritical water (SBCW) between 130 and 170 °C is measured. The solubility of naproxen in SBCW was correlated to temperature using a Modified Universal Functional Activity Coefficient (M-UNIFAC) model. Errors in the model were minimized by optimizing the water-carboxylic acid interaction parameter, as other side groups were already optimized. The micronization of naproxen via processes that used the tunable solvent power of SBCW was conducted. Two precipitation techniques were developed. In the first technique, the temperature of a SBCW solution containing naproxen was rapidly quenched by injection into cold water solutions. The quenching media were either pure water or 1% w/v solution of lactose in water. Variations in SBCW-naproxen solution injection temperature and supersaturation ratios in pure water were examined. Product morphology was robust toward changes in operating conditions and consisted of flaky crystals with a particle size distribution ranging from 0.5 to 100 µm. Under specific experimental conditions, naproxen crystals formed spherical agglomerates. Particles produced from lactose/water solutions were slightly smaller than those produced from pure water. In the second technique, precipitation was induced by vaporization of SBCW-naproxen solutions. The SBCW solutions were injected into a vessel that was connected to a vacuum pump. The process generated large naproxen microcrystals with broad particle size distributions. 1. Introduction Subcritical water (SBCW) has been used as a solvent to dissolve an array of hydrophobic organic compounds (HOCs). The ability to dissolve a variety of HOCs stems from the dependence of water polarity on temperature. It has been shown that the polarity of water is effectively halved from 25 to 200 °C.1 Therefore, polar compounds that are regularly water insoluble at ambient temperature may become soluble under subcritical conditions. The tunable properties of water have been used to separate mixtures of antioxidants and polycyclic aromatic hydrocarbons (PAHs).2-4 It has been shown that the solubility of different HOCs can increase by up to 7 orders of magnitude between 100 and 200 °C.3,5 Extraction technologies have capitalized on the tunability of the solvent power of water to process semi- to nonpolar organic compounds. The yield of extraction processes are typically determined by the solubility of the organic compounds. In general, oxygenated organic compounds exhibit higher solubilities in SBCW than nonoxygenated organic compounds.5,6 As a consequence, processes using SBCW as a solvent can produce higher throughputs when applied to oxygenated organic compounds. Many active pharmaceutical ingredients (APIs) contain oxygen, thereby indicating the potential use of SBCW in pharmaceutical sectors. SBCW has been used for the synthesis, separation, extraction, and precipitation of APIs and excipients.7,8 The use of SBCW solvent technology for APIs includes HPLC or other solventseparation based assays to rapidly screen potential drug candidates and for quality control purposes.9 The use of SBCW for the micronization of APIs was demonstrated by precipitating the antifungal drug griseofulvin.10 In this work, the SBCW precipitation method was extended to the processing of the antiinflammatory agent naproxen. Two process embodiments were * To whom correspondence should be addressed. E-mail: n.foster@ unsw.edu.au. Fax: +61 2 9385 5966.

designed. In one case, water was used both as a solvent (at subcritical conditions) and as an antisolvent (at room temperature and moderate pressure). The effect of lactose as a crystal growth modulator was tested. A spray method was also devised, by which the mechanism of precipitation was by solvent vaporization rather than tuning of the solvating properties of the solvent. The spray method would be of interest when a dry powder formulation is required as it overcomes the need for a subsequent drying step. It is necessary to carry out solubility studies on systems that employ rapid precipitation to produce particles.11 The solubility of naproxen in SBCW was, therefore, established. A model of the solubility is also presented using a recently developed modified universal functional activity coefficient (M-UNIFAC) model.12 Corrections are applied to reconcile model outputs to the solubility data. 2. Methods a. Materials. Naproxen (98%) and anhydrous lactose were purchased from Fluka. Reagent grade acetone was purchased from UNIVAR. Deionized water was used for all experiments. b. Processing Method. i. Solubility Determination. A number of studies on the determination of solubility in SBCW using dynamic systems have been reported.3,5,6,13 In this study, a batch method was devised to determine the solubility of hydrophobic compounds in SBCW. The construction of a batchtype method allowed for easier transformation of the solubility apparatus to a rapid precipitation apparatus. A schematic of the experimental apparatus is shown in Figure 1. 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. In order to prevent the flow of undissolved solute or melted

10.1021/ie9019825  2010 American Chemical Society Published on Web 08/31/2010

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Ind. Eng. Chem. Res., Vol. 49, No. 19, 2010

Figure 1. Schematic of the solubility apparatus.

Figure 2. Filter setup at the ends of the SV.

liquid through SV, two stainless steel filter pieces were added to the fittings at either end of the SV. A diagram of the filter setup is shown in Figure 2. During the vessel operation near or at the melting point of naproxen, it was assumed that the melt would be too viscous to flow through the filter and packing material with the low pressure differential between the SV and the collection tubing. Typically, melted pharmaceutical compounds require pressure differentials of at least 100 bar to be extruded through 1 mm frits.14,15 The pressure differential in the system tested in this work was at most 50 bar. Thus, the pressure required to extrude a melted solid through the 0.5 µm filter frit placed over the exit chamber would be much higher than the pressures used in the system here. Furthermore, inspection of the frit postprocessing indicated that the undissolved naproxen was left at the base of the filter frit. For each run, the SV was loaded with naproxen (200 mg). The vessel was then 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. While pressures as low as 25 bar could be used at 170 °C to keep water in the liquid state, 70 bar was used to ensure that at all points throughout the experiments water would not vaporize. The system was brought to the selected temper-

ature using the GC oven with pressure from thermal expansion relieved through V4. Once the set temperature was reached, 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 driven by an electric motor. The external ring magnet oscillated at 72 strokes per minute. After 10 min of 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 constant vessel pressure, thereby preventing the vaporization of SBCW inside the apparatus during product collection. Valve V4 was opened slightly to permit the slow flow of SBCW solution into a preweighed capped vial. Once nitrogen started to flow into the collection vial, V4 was shut and the oven was turned off. 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 naproxen. Acetone solutions were collected in a separate preweighed vial. The contents of both vials were dried for 24 h: water suspensions were dried in an oven at 50 °C, while acetone solutions were dried in air. Vials were then reweighed, and the amount of water and naproxen extracted from the system were assessed. Thermogravimetric analysis (TGA) confirmed the quantitative removal of solvents. Each experiment was repeated a minimum of four times to ensure reproducibility. The stability of naproxen upon processing was assessed on samples treated at temperatures above 200 °C by Fourier transform infrared (FTIR) spectroscopy using the KBr disk method. The solubility readings of the apparatus were validated against literature solubility data using anthracene as the test chemical. Validation of the solubility results in the batch solubility apparatus has been done in a previous publication.10 ii. Injection into Cold Water Particle Formation Method. A schematic of the equipment used is shown in Figure 3. A tee permitted the flow of SBCW solution from the SV to a collection vessel where precipitation occurred. The line to the precipitation vessel was 1/16 in. OD stainless steel tubing. The


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Figure 3. Subcritical water particle formation apparatus.

line was located inside the oven to minimize temperature changes prior to the particle formation vessel. A nozzle with an ID of 1 mm was used to deliver the SBCW solution into the particle formation vessel. The flow from the SV to the precipitation vessel was controlled by V3 (Figure 3). The collection vessel (PC) was filled with 60 mL of water at room temperature, and a backpressure of 20 bar was applied to ensure that the water remained in the liquid state throughout the experiment. A weighed amount of naproxen was loaded into the SV. The system was filled with water, and 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 PC vessel. 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 maintained. The content of the PC vessel was collected 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. The effect of injection temperatures of the SBCW solution and of the presence of lactose in the precipitation vessel were investigated. The SBCW-naproxen solutions were prepared at 130, 160, and 170 °C. Lactose/water solutions were prepared by dissolving 1% w/v lactose in deionized water. To investigate the effect of lactose on product morphology, 60 mL of the solutions were placed inside the PC vessel. iii. SBCW-Solute Spray Particle Formation Method. A spray apparatus was devised and is shown schematically in Figure 4. A 150 mL stainless steel capture vessel (SB) was fitted at the outlet of V2 inside the oven. The outlet of the SB was connected to 1/8 in. stainless steel tubing fitted with a 0.5 µm filter stone. The tubing was connected to a venturi tube attached to a water supply. The venturi tube provided a maximum vacuum of 17.5 mmHg. The purpose of the vacuum was to assist in the vaporization of the injected solution.

The precipitate was collected from the SB after the system had cooled to room temperature. In some cases, water was not completely removed from the precipitate and the powder was dried further by a flow of warm air (30 °C) for 5 min. c. Scanning Electron Microscopy and Laser Scattering (LS) Methods. A Malvern Mastersizer S was used to determine the particle size of naproxen. Particle size and size distribution (PSD) analyses were carried out on suspensions taken directly from the particle formation vessel. Samples produced via the spray technique were captured by washing the internals of the SB with distilled water; the resulting suspension was collected and analyzed. Results are reported as a number mean diameter (X50) of a distribution. A Hitachi S900 SEM (scanning electron microscope) 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. d. X-ray Diffraction Method. The X-ray diffraction (XRD) machine used was a Philips multipurpose X-ray diffraction system (MPD). The naproxen 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 patterns of the processed materials were analyzed and compared to the diffraction patterns of the raw material to evaluate changes in the crystal structure. e. Differential Scanning Calorimeter Method. A TA Instruments differential scanning calorimeter (DSC) 2010 was used. Dried powder samples (5-10 mg) were loaded into the 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. f. M-UNIFAC Modeling Method. The assumptions and equations that comprise the UNIFAC, M-UNIFAC, and Fornarimodified M-UNIFAC models can be readily found in the published literature.12,16-19 The optimization of group parameters was done by minimizing the error of the solubility data and the solubility model. Error reduction was carried out in Microsoft Excel using the Goal Seek function.

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Figure 4. Spray apparatus for the formation of dry particles from SBCW solutions. Table 1. Solubility of Naproxen in SBCW pressure temperature solubility compound (bar) (°C) x2a (×107) SDb (×107) reference naproxen

a

1.013 70 70 70 70 70

25 130 140 150 160 170

0.550 40.90 186.3 204.5 179.1 556.3

20 3.03 25.8 28.2 8.57 35.7

x2, mole fraction. b Standard deviation.

b. Solubility Models. The solubility curve produced by the MF-UNIFAC model for naproxen (Figure 5) was an underestimate of the true experimentally measured solubility, both at ambient and subcritical conditions. An investigation was carried out to establish whether changing a parameter of the M-UNIFAC model with updated oxygen-water interaction terms could reconcile the model to the data. Two different oxygen types exist in naproxen according to the division used in the M-UNIFAC model: a carbonyl group and a carboxylic acid group. Recently, the solubility of a number of oxygenated organic compounds containing ether and carbonyl side groups was investigated by Kara´sek et al.5 The pure solute property data at room temperature from the literature was used to predict the solubility of these compounds using the MFUNIFAC model. In order to compare the solubilities, the error of each compound was calculated according to eq 1, where x is the mole fraction of the solute. The subdivision of UNIFAC Table 2. MF-UNIFAC Model of Xanthenes, Anthrone, Xanthene, and 9, 10 Anthraquinone xanthene anthrone xanthone 9,10 anthraquinone

n (Ghmeling) subgroup 2 3 3 10 13

Figure 5. Solubility of naproxen in SBCW at 70 bar from 25 to 170 °C. Experimental data (9), M-UNIFAC model (- · · -), and MF-UNIFAC model (-).

3. Results and Discussion a. Solubility. The solubility behavior of naproxen is shown in Table 1. The solubility data is compared to model outputs in Figure 5. Naproxen exhibited a solubility plateau from 140 to 160 °C. The DSC show that both the raw and processed naproxen (shown in Figure 9) melt between 140 and 160 °C. Thus, the solubility plateau and the naproxen melting occur over the same temperature range. It is possible that, over the temperature range of 140 °C-160 °C, complex interactions take place which involve water and melted and solid phase naproxen.

Vk

Vk

Vk

Vk

1 4 8 1 0

1 4 8 0 1

0 4 8 1 1

0 4 8 0 2

CH2 ArC ArCH CHO CH3O

# subgroups dHmelt Tmelt reference

xanthene

anthrone

xanthone

9,10 anthraquinone

Vk

Vk

Vk

Vk

14 19200 373.7

14 26800 428.15

14 26120 434.1 5

14 32570 558

errors T/°C

xanthene

anthrone

xanthone

9,10 anthraquinone

40 60 100 140 160

6% 7%

2% 0% 3% 4%

1% 3% 8% 10% 9% average SD

1% 4% 10% 15% 16% 6%


Figure 6. Chemical structure of naproxen. Table 3. M-UNIFAC Side-Group Division for Naproxen subgroup

Vk

CH3 ArC ArCH ACCH CH3O COOH # subgroups dHmelt23 Tmelt23

1 3 6 1 1 1 14 32927.18 429.15

Table 4. Original and Fitted Water-Carboxylic Acid (Side Group 11,18 on Gmehling18) and Carboxylic Acid-Water (Side Group 18,11) Interaction Parametersa original M-UNIFAC (11,18) fitted M-UNIFAC (11,18) (18,11) COOH-H2O H2O-COOH (18,11) COOH-H2O H2O-COOH a b c

624.97 -4.6878 5.24 × 10-3 a

-1795.2 12.7080 -1.55 × 10-2

624.97 -4.6878 4.24 × 10-3

-1795.2 12.7080 -1.69 × 10-2

The letters a, b, and c represent M-UNIFAC parameters.

side groups is shown in Table 2, where n is side-group number as shown in Gmehling et al., Vk is the number of side groups in the molecule, dHmelt is the heat of melting of the solute, and Tmelt is the melting temperature of the solute. Error(%) )

|

|

lnxactual - lnxmodel × 100 lnxactual

(1)

The model could predict the solubility of the oxygenated compounds anthone, xanthone, anthrone, and 9, 10 anthraquinone with an average error of 6% (Table 2). While it may be seen that the error increases with temperature, it should also be noted that the solubility data published by Kara´sek et al. is typically lower than other literature data at higher temperatures (such as the solubility data published by Miller et al.).21,22 The results indicate that the estimated values of the interaction parameter

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for the carbonyl group produced satisfactory results in predicting solubilities in SBCW. In this work, a new estimate of the carboxylic acid (COOH)-water interaction parameter was calculated by minimizing the error between the model and the experimental data. The chemical structure of naproxen is shown in Figure 6, and the division of the M-UNIFAC subgroups is shown in Table 3. The interaction parameters of the M-UNIFAC model and the naproxen-optimized M-UNIFAC model are shown in Table 4, where a, b, and c are the Ghmeling defined empirical interaction parameters of the carboxylic acid side group (18) and water (11). The dHmelt and Tmelt values were determined for the raw material by integrating the area under the melting peak of the DSC curve. The results of the adjusted M-UNIFAC model parameters are shown in Figure 7. The average error (from room temperature to 170 °C) was reduced from 28% to 5%. It was not possible to reproduce the apparent solubility plateau between 140 and 160 °C using the M-UNIFAC model. It was not possible to determine whether this fit improves the prediction of the solubility of other carboxylic acids in SBCW from published data. Solubility data exists for some organic compounds (fatty acids) with carboxylic acids in subcritical water.24 However, the solubility of these compounds in SBCW cannot be modeled beyond 100 °C, because they melt at, or below, 100 °C.12 c. Precipitation SBCW-Solution Spray into Pressurized Cold Water. The experimental conditions for the precipitation experiments are summarized in Table 5. Each experiment was carried out in duplicate or triplicate. In experiments 3 and 4, the particle morphology was unimodal and had a broad particle size distribution (between 0.5 and 100 µm). Flake-plate crystals were precipitated (shown in Figure 8a). Similar morphologies of naproxen have been precipitated in supercritical antisolvent (SAS) processes using ethanol and acetone as solvents and carbon dioxide as the antisolvent.25 The particle sizes produced in this work were similar to those produced in the supercritical antisolvent process with acetone as a solvent (particles precipitated using ethanol as a solvent in the SAS technique were the same morphology as those precipitated from acetone). The light scattering results were typically larger than the average particle size established from the SEM results, as shown

Figure 7. Solubility of naproxen in SBCW at 70 bar (∆) and MF-UNIFAC model (-) with optimized carboxylic interaction parameters.

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Table 5. Experimental Conditions and Results Summary injection conditions (of the hot water solutions)

experiment 3 4 5 6 7 8 a

T (°C) 140 160 170 140 160 170

concentration (mole fraction) 186.3 179.1 556.3 179.1 186.3 556.3

results collection conditions (in PC) a

W W W WLb WL WL

max. length (µm, SEM)

max. length aggregates (µm, SEM)

15 12 2 3 2 2

15 15 15 15 12 20

X50 (µm, LS)

morphology

20 ( 0.10 30 ( 0.15 17 ( 0.09 20 ( 0.10

flake crystals flake crystals and some wrapped spheres wrapped-flake crystal spheres plate crystals plate crystals spheres

29 ( 0.15

W: Injected into a distilled water at 20 bar and 21 °C. WL: Injected into 1% w/v lactose in distilled water at 20 bar and 21 °C. b

Figure 8. Precipitates of naproxen at experimental conditions (a) 3, (b) 5, (c) 6, and (d) 8.

in Table 5. In some cases, the SEM images showed that particles tended to aggregate into clumps. An average aggregate particle size was reported on the basis of aggregated particles observed in the SEM images (Table 5). Experiments 3 and 4 were conducted at conditions where the concentrations were similar and temperatures differed by 30 °C (Table 1). The effect of temperature on the product morphology was negligible. The concentration of naproxen in the SBCW solution affected the size of the precipitates. The size of the naproxen crystals produced for saturated solutions at 170 °C (experiment 5) were up to 1/10th the size of the particles precipitated from saturated solutions at 140 °C. The same trend has been observed from previous precipitation studies of griseofulvin from SBCW solutions.26

Experimental condition 5 also resulted in the formation of flaky crystals wrapped into spherical agglomerates, as shown in Figure 8b. The DSC curve of the crystals precipitated in plain water at 140 and 170 °C were identical. Crystals that agglomerated into spheres have been precipitated from crystallo-co-agglomeration techniques (CCA).27 The CCA technique was designed to precipitate crystals around droplets of a wetting agent. For spheres to form, the droplets of the wetting agent needed to be much larger in diameter than the precipitated crystals.28 Otherwise, agglomerates would form around the wetting agent in nonordered clumps. It is unlikely that the spheres formed in our work were the result of aggregate formation around droplets. The injected jet of the SBCW-naproxen solution does not form droplets around


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Figure 9. DSC of naproxen raw ( · · · ) and precipitated from SBCW without lactose (---) and with lactose (-).

Figure 10. XRD patterns of naproxen produced at different processing conditions and unprocessed naproxen.

which the solute can precipitate. Absence of droplet formation was observed in the product collection chamber through the view window. Furthermore, the requirement for droplets to form are that both the injected and capture liquids need to be immiscible. Hot and cold water are miscible; therefore, it is unlikely that droplets would form. With no droplets formed during the injection of the jet, the mechanism for spherical particle agglomeration is not possible. Spherical crystal agglomerates of API particles have also been formed by spray drying suspensions of ciprofloxacin particles.29 It was shown that, as the distance between the particles was reduced, small spherical agglomerates were formed. It is likely that the spherical naproxen agglomerates formed in a similar way to the spray drying technique. At 170 °C, the

supersaturation ratio of the injected SBCW-naproxen jet was higher than at 140 °C. The higher supersaturation ratio corresponded to a closer proximity of newly formed particles. The result of closely spaced precipitates led to an agglomeration of naproxen particles into spheres. d. Precipitation into a Lactose-Water Solution. The addition of lactose into the collection chamber (for experiments 4-6) resulted in smaller particles. The crystals precipitated were visibly different from the crystals produced in experiments 3 and 4, as shown by the SEM images in Figure 8c. The thermal properties of the crystals precipitated in the presence of lactose differed from the crystals precipitated without lactose (Figure 9). In particular, the melting peak of

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Table 6. Experimental Conditions and Results of Naproxen Micronization by Injection of SBCW Solutions into a Heated Vacuum Chamber injection conditions experiment

T (°C)

concentration (mole fraction)

1 2

140 170

179.1 556.3

the naproxen precipitated in the presence of lactose was sharper than the naproxen precipitated without lactose. While the melting peak of the naproxen precipitated with lactose was 3.6 °C lower than naproxen precipitated without lactose, the onset of melting occurred at the same temperature for all samples. The presence of lactose did not substantially affect the XRD patterns of the micronized naproxen crystals that were similar to the XRD profiles of the raw material, as shown in Figure

Figure 11. Precipitate collected from SBCW-naproxen solution spray into a vacuum vessel.

results diameter (µm, SEM)

diameter (µm, LS X50)

morphology

10-500 50-500

20 25

flake crystals flake crystals

10. Thus, the crystal phase of naproxen precipitated in the presence of lactose was the same as the raw naproxen and the naproxen precipitated into pure water. The narrowing of the melting curve indicates that the crystals precipitated in the presence of lactose had a more ordered structure than the crystals precipitated without lactose.30 It is likely that lactose acted as a crystal growth promoter for naproxen. The hydrophilic nature of the lactose present in the precipitation chamber may have drawn water away from the hydrophobic bonding sites during precipitation, allowing for a more ordered naproxen crystal to form.31 The presence of lactose during the precipitation from a 170 °C solution jet did not hinder the formation of spherical crystal agglomerates. Thus, lactose did not affect the formation of naproxen spheres. Lactose was effective in reducing the particle size of the product, indicating that there is scope to widen the study of the effect of different excipients and their concentration levels on product morphology. Ideally, the compounds selected will be acceptable components of pharmaceutical formulations. e. Precipitation by SBCW-Solution Spray into a Vacuum Chamber. The experimental conditions and results for the injection of naproxen solutions in SBCW into a heated vacuum chamber are shown in Table 6. The spray process (experiments 1 and 2) produced flake-plate crystals, as shown in Figure 11. There was no difference between the particles precipitated at 140 and 170 °C. The particle size distribution is shown in Figure 12. The crystals that were precipitated using the SBCW spray process were similar to the crystals that have been precipitated from supercritical fluid antisolvent techniques, in which acetone was used as the antisolvent.25 The particle size distribution was bimodal, as shown in Figure 12. In some cases, water remained in the collected product. The slow cooling of the remaining water inside the bomb may have precipitated larger naproxen crystals. Modifications of the system to incorporate improvements are being investigated. Improvements being investigated include the use of a hot fluid flow to aid more rapid powder drying. 4. Conclusion

Figure 12. Particle size distribution of naproxen precipitated by the spray technique at 160 °C.

The solubility of naproxen has been established and modeled using the M-UNIFAC model with optimized carboxylic acid and water interaction parameters. Naproxen was precipitated in three different precipitation environments. It was found that the morphology of the precipitated particles was dependent upon the degree of supersaturation of the SBCW solutions. Crystalline flaky particles with a maximum aggregate size of 20 µm were produced using water solutions at room temperature and low pressure as a quenching medium and antisolvent. Spherical crystal agglomerates were produced at 170 °C. The addition of lactose in the precipitation chamber produced smaller particles and did not hinder the formation of spherical aggregates at higher temperatures, nor changed the polymorphic form of the product. Results indicate that there is scope to extend the investigation of the effect of crystal growth modulators to other compounds and concentration levels.


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ReceiVed for reView December 14, 2009 ReVised manuscript receiVed June 28, 2010 Accepted August 20, 2010 IE9019825

Solubility, Solubility Modeling, and Precipitation of Naproxen from

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