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Preparation of naproxen–excipient formulations by CO2 precipitation on a slurry
Powder Technology 255 (2014) 80–88
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Powder Technology journal homepage: www.elsevier.com/locate/powtec
Preparation of naproxen–excipient formulations by CO2 precipitation on a slurry P. Subra-Paternault a,⁎, P. Gueroult b, D. Larrouture b, S. Massip c, M. Marchivie c a b c
CBMN — UMR 5248, Université Bordeaux 1 — IPB, Bât 14, Allée Geoffroy Saint Hilaire, 33600 Pessac, France Laboratoire de Technologie Pharmaceutique Industrielle, UFR Pharmacie, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France Laboratoire de Pharmacochimie, CNRS FRE 3396 UFR Pharmacie, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
a r t i c l e
i n f o
Available online 18 September 2013 Keywords: Formulation Crystallization Supercritical CO2 Mannitol Silica Naproxen
a b s t r a c t The work focused on screening the impact of various excipients and/or procedure in a new method that consists in a CO2-induced precipitation of a drug on a slurry. Naproxen (NPX) is a drug whose bioavailability could be improved by formulation with hydrophilic excipients. The investigated excipients were of various type, size and porosity, i.e. mannitol, silicas (SiO2 and SIO2 aminopropyl) and an anion exchange resin Duolite. The precipitation process used compressed CO2 as antisolvent for NPX and acetone as solvent to dissolve NPX and to suspend the excipient particles. Naproxen precipitated as crystals with a size distribution influenced by the NPX:excipient ratio for mannitol-based formulations. For other excipient co-precipitates, the overall size distributions were in the same range and below 330 μm except for the 5 μm silica. Due to the hydrophilic nature of the excipients, most formulations yielded an increased drug dissolution rate. Compared to physical mixtures, the benefit of the CO2 treatment was demonstrated in case of the excipient mannitol. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The use of excipients for manufacturing pharmaceutical products is a common practice of pharmacotechny. A challenge is to avoid the agglomeration of the active molecules in order to maintain the formulation uniformity. Besides improving the powder flowability, excipients can be used as diluent, binder, disintegrating, dispersing, gliding, lubricant agent [1–5]. One main development in pharmacy is to increase the bioavailability of compounds belonging to BCS Class II and Class III (Biopharmaceutics Classification System [6]), and specially of active pharmaceutical ingredient (API) whose bioavailability is restricted by a low solubility in biological fluids. The improvement can be realized by modifying the API characteristics like reducing the particle size or altering the crystal habit, or by adding a water-compatible ingredient which can complex or entrap the drug (surfactants, resins…) [7]. A particular way consists of using porous structures in which the drug could penetrate, as in the case of mesoporous silica that can take up to 40 wt.% of Ibuprofen [8]. The API is often dispersed in an amorphous form, which, combined with a better wettability of the silica-API structure in comparison with the API alone, leads generally to an increase of the API dissolution rate [9]. In pharmaceutical industry, the obtaining of active molecules in the form of powder is dominated by operations carried out in solution as crystallization, precipitation or synthesis. Meanwhile, new perspectives of API micronization or formulation are offered by using supercritical ⁎ Corresponding author. Tel.: +33 5 40 00 68 32. E-mail address: [email protected] (P. Subra-Paternault). 0032-5910/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.powtec.2013.09.012
fluids and mainly CO2 to partially or totally replace solvents [10–12]. Totally avoiding the solvents in the preparation of API formulations is difficult or at least it is restricted to few molecules soluble enough in supercritical CO2 to envisage sorption in porous carriers [13–15]. So far, many molecules are micronized by using CO2 as an antisolvent, a process in which CO2 is added to an initial solution to decrease the solubility of the molecule in the newly CO2 -solvent mixture and to provoke therefore the molecule precipitation [16–19]. On the same principle, this work develops the coupling of precipitation and in-situ formulation by adding the excipient as solid particles to the initial solution. Therefore, the process corresponds to a precipitation on slurry. It is worthwhile noting that literature reports many examples of API and polymer coprecipitation, but precipitation on suspension is rare. Developed initially by Thakur et al with silica as additive and griseofulvine as drug [20], we extended the concept to the more complex formulation of API + polymer + silica [21]. One can expect for the excipient to act, at a minimum as a deagglomerating agent for the API particles or as a more active carrier if API molecules are physically sorbed or entrapped when porous structures are selected. But presence of solid particles in the precipitation medium can also impact the precipitation behavior of the drug, since any substances other than the material to precipitate may act as an impurity and therefore possibly affect the nucleation and growth behaviors [22]. In this work, the selected API is naproxen, a non-steroidal antiinflammatory compound whose bioavailability could be improved by the use of hydrophilic excipients. The selected excipients are nonporous polyol (mannitol), two silicas of different porosity, size and functionality (SiO2 and SiO2 aminopropyl) and a granular Duolite® resin.
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Mannitol is widely used in pharmaceutical formulations due to its Generally Recognized as Safe (GRAS) status. It is typically used as bulking agent due to its high aqueous solubility, as diluent in rapidly dispersing oral dosage forms or as a carrier in dry powder inhalers [23]. Nanoporous silicas with controlled three-dimensional silicate structure (Sylysia in [15]) or nanometric size (Aerosil in [24]) are usually employed for enhanced bioavailability formulations. For availability and to avoid manipulating nanoparticles, we have selected silica particles larger than 5 μm that are typically used in chromatographic applications. Duolite® is a crosslinked water-insoluble anion exchange resin suitable for pharmaceutical applications either as an active ingredient or as a carrier for anionic drugs [25]. Derived from a copolymer of styrene and divinylbenzene, this resin offers complex interactions with naproxen via the benzene and ammonium functionalities. Regarding CO2 processing, pure naproxen has been precipitated from acetone [26] thanks to the solubility behavior in CO2 + acetone mixture [27]. Accordingly, the formulation process was carried out with acetone as initial liquor, under mild conditions of temperature (27 °C) and pressure (10 MPa). A low temperature process was selected to promote lowenergy conditions and because of the lower solubility of compounds in pure solvent or CO2-expanded solvent [28,29]; otherwise, CO2 might be a too weak antisolvent to induce a significant precipitation. All excipients were insoluble in acetone, so the initial liquor contained dissolved naproxen and the excipient particles that were maintained in suspension by a stirrer. The produced formulations were characterized for their crystallinity, particle size distribution, naproxen content and dissolution kinetics. For comparison purposes, CO2 essays without solvent were performed under conditions of higher pressure and temperature to promote naproxen solubilization. The goal of this dry route was also to realize an intimate mixing between the two powders.
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composition of the CO2-acetone mixture is given by the experimental curve displayed in Fig. 1 as well. By getting enriched in CO2, the liquid phase attained a composition in which the naproxen was not soluble anymore and thus precipitated. CO2 was added until a pressure higher than the mixture critical pressure was obtained, i.e. 10 MPa. A flux of fresh CO2 was next maintained through the vessel for 60 min in order to dry the particles while the vessel was heated to 36 °C to help at the solvent removal. After depressurization, the product was collected, weighed and characterized. In dry experiments carried out without organic solvent, NPX and excipient powders were introduced in the vessel and CO2 added at 57 °C up to 18 MPa to promote solubilization of naproxen. Ingredients and CO2 were kept in contact for 2 h under a stirring of 500 rpm. 2.3. Powder characterization 2.3.1. Morphology and particle size distribution (PSD) Morphology was observed par optical microscopy (Olympus BX51, model BX51TF, magnification ×10) and recorded by a ColorView UCMAD3 camera. Size distribution was measured by laser diffraction using a MasterSizer 2000 (Malvern) equipped with a low volume circulation device and SDS 0.3% as dispersion medium. Measurements were recorded every 5 min during 30 min. Since mannitol is highly soluble in water, the PSDs of mannitol-based formulations reflect only the naproxen sizes. 2.3.2. Crystallinity (XRD) Crystallinity was assessed by X-ray diffraction (XRD) of samples deposited on a stainless steel or silicium holder, using a D5005 Siemens diffractometer. Data were collected for 2θ angles of 3–40°, with a step size of 0.02° at a scanning speed of 0.06°/min.
2. Materials and methods 2.1. Materials Naproxen (NPX, 98% purity) was purchased from Sigma-Aldrich. Acetone (ACE, 99.8% purity) and CO2 (99.5% industrial grade) came from VWR and Air Liquide (France), respectively. Various excipients were used: mannitol (Parteck® Delta M, gifted by Merck; crystalline tablets below 50 μm in length (MNol)); porous silica of 5 μm mean size (SiO2 UltiPrep300, Interchim, France; spherical particles, 300 Å of pore diameter (UP)); aminopropyl-functionalized silica (Sigma-Aldrich, particles of 40–63 μm, pores of 60 Å (Si-NH2)); Duolite® (Rohm and Haas, copolymer of styrene and divinylbenzene and a quaternary amine, coarse particles of 1–400 μm, amorphous (duol)). Chemical formulae and micrography of raw materials are given in Table 1. 2.2. Experimental set-up and procedure Experiments were carried out in a batch GAS apparatus schematized in Fig. 1. Details of the equipment can be found elsewhere [17]. Briefly, the precipitation unit is a 0.490 L vessel equipped with sapphire windows and pressure and temperature sensors. The vessel temperature is controlled by electric heating tape (Tset of 27 °C). A stirrer ended by a Rushton-type turbine plunges into the solution. The CO2 introduced by a Lewa pump is dispersed into the solution through the holes of the turbine. Additionally, the stirrer maintains the excipient particles in suspension (R of 500 rpm). A stainless steel filter (porosity 5 μm) overtopped by a membrane disk of 0.22 μm in porosity collects the produced particles at the vessel bottom. In a typical experiment, the suspension was prepared by first dissolving 2 g of naproxen in 45 ml of acetone (C ≈ 0.34 Csat) and adding 1 g, 2 g or 4 g of excipient. The suspension was sonicated for 15 min and poured into the vessel. The CO2 was progressively introduced, inducing an increase of the vessel pressure and the enrichment of the liquid phase in CO2 according to the liquid–vapor diagram given in Fig. 1. The evolution of the overall
2.3.3. Naproxen content in formulations The powder samples were dispersed in acetone and diluted for monitoring the drug content by spectroscopy (Spectrometer UVIKON XS, Secomam). Naproxen was detected at a wavelength of 332 nm. A calibration curve between 0.032 and 0.12 mg/ml of NPX in acetone was first built. 2.3.4. Dissolution Dissolution kinetics of produced powders were continuously monitored using the USP 2 paddle method according to [30] and the online monitoring developed for tolbutamide release [21]. The dissolution medium consisted of 900 ml of 0.3% SDS water maintained at 37.0 °C and 30 mg equivalent NPX was added to the medium stirred at 50 rpm by a paddle. The drug release was monitored continuously by UV at 332 nm (UVIKON XS, Secomam) thanks to a peristaltic Heildorph pump that allowed for circulating the bulk solution through the UV flow cell. Few samples were also analyzed by a flow-through apparatus [31]. The flow-through apparatus (Eur.Phar. 7) consisted of a 2 L -reservoir of dissolution medium and Sotax pump that delivered the dissolution medium through the sample cell (22.6 mm i.d.) at 19 ml/min. The flowthrough cell that contained 10 mg equivalent NPX was maintained at 37.0 °C. A spectrophotometer equipped with a UV-flow cell monitored the NPX content at 232 nm. The dissolution medium consisted of phosphate buffer at pH 6.7. 3. Results and discussion Conditions and product characteristics are given in Table 2. Conditions and API:excipient ratio were selected on the basis of preceding results with silica [21] or of particle generation upon operating conditions [17]. The work focused on screening the impact of various excipients and/or procedure on the physical and dissolution characteristics of powders prepared by this new method for which literature background is rare. It is well known that smaller particles exhibit faster dissolution rate because
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Table 1 Naproxen and excipients used for CO2 induced formulations from acetone. Duolite structure from [25]. Soluble in acetone
Soluble in water
Naproxen (NPX)
Formula
Aspect of raw materials
Yes
Low
Mannitol (MNol)
No
Yes
Aminopropyl silica (SiNH2)
No
No
Silica (SiO2)
No
No
Duolite®
No
No
of their increased surface area [7]. Naproxen, in other hand, is quite soluble in acetone–CO2 mixtures [28,29], hence is prone to precipitate with large size because of the low obtainable level of supersaturation [22]. Conditions of GAS process were therefore selected in view of favoring smaller sizes [32], i.e. a low temperature of 27 °C, a vigorous stirring of 500 rpm and a fast introduction rate around 0.6–0.8 MPa/min. Naproxen was first precipitated as a single species from acetone, i.e. with no suspended excipient. The drug was recovered with a yield of 50% that indicated a quite high solubility in the CO2 + acetone mixture. The powder was granular with agglomerates that clung to a spatula and that were difficult to disperse for the observation by microscopy. Naproxen particles appeared as bright elongated particles with length of several hundreds of micron (Fig. 4a); many particles were also large,
with widths around 100 μm up to 320 μm. When co-processed with excipient in the ratio of 2:1, the produced powders contained about 70% ± 5% of naproxen, which was higher than the expectations based on the 50% yield of precipitation of run #1. Hence, the presence of particulate material in the solution improved the precipitation yield, but was irrespective of the excipient type so it did not depend on potential interactions of the API with the particles. Moreover, the produced powders with excipients showed enhanced flowability when compared to the single-processed drug. Although no quantitative analysis of flowability was performed, visual inspection with naked eyes during the transfer of samples from the storage flask to the microscope slide provided a qualitative evaluation: powders with excipients clung less to the spatula and were more dispersable on slide than single-processed drug.
Fig. 1. Experimental CO2 set-up and CO2 + acetone phase diagram in which the evolution of the overall composition upon the CO2 introduction is shown. Symbols = experimental data of run #7; dotted lines = liquid–vapor phase diagram.
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Table 2 Conditions and characteristics of CO2-produced formulations. Precipitation on excipient slurry; Vacetone = 45 ml, T = 27 °C, R = 500 rpm, Pfinal = 10 MPa. Dry mixing: T = 57 °C, R = 500 rpm, Pfinal = 18 MPa, contact time = 2 h. Physical mixture: hand-shaking a mixture of unprocessed NPX and the excipient. API–Excipient = Initial amount of naproxen and excipient; %NPX = content of NPX in produced powder (wt.%); Cx = crystalline form of naproxen; d50/d90 = characteristic diameters of the particle size distribution. Dissolution kinetics: t90 = time corresponding to 90% of dissolution; R60 = % of dissolution at 60 min. Mixture #
API–excipient
Protocole
% NPX
Characteristics
Unprocessed NPX NPX #1
– 2g
– Pure NPX precipitation
100% 100%
Cx; d50/d90 = 20 ± 5/242 ± 33 μm; t90 = 112 ± 28 min; R60 = 80 ± 5% Cx; d50/d90 = 118 ± 16/693 ± 188 μm; t90 = 190 ± 13 min; R60 = 69 ± 2%
Excipient = Mannitol NPX–MNol #2 2 NPX–MNol #3 2 NPX–MNol #4 2 NPX–MNol #5 2 NPX–MNol #6 1 Physical mixture
Precipitation on slurry Precipitation on slurry Precipitation on slurry, faster CO2 introduction Precipitation on slurry, faster CO2 introduction Dry route Shaking
73% 48% 71% 38% 53% 75%
Cx; d50/d90 = 152 ± 23/445 ± 35 μm; t90 = 48 ± 4 min; R60 = 95 ± 2% Cx; d50/d90 = 68 ± 7/235 ± 33 μm; t90 = 15 ± 1 min; R60 = 98 ± 1% Cx; d50/d90 = 54 ± 2/203 ± 37 μm; t90 = 17 ± 7 min; R60 = 100 ± 1% Cx; d50/d90 = 66 ± 15/226 ± 23 μm; t90 = 15 ± 1 min; R60 = 98 ± 1% Cx; d50/d90 = 22 ± 3/220 ± 29 μm; t90 = 15 ± 1 min; R6o = 98 ± 1% t90 = 70 min; R60 = 89%
Excipient = Duolite® NPX–duol #7 2 g–1 g NPX–duol #8 1 g–1 g Physical mixture
Precipitation on slurry Dry route Shaking
70% 46% 70%
Cx; d50/d90 = 74 ± 4/223 ± 23 μm; t90 = 38 min; R60 = 94% Cx; d50/d90 = 73 ± 11/226 ± 22 μm; t90 = 42 min; R60 = 94% t90 = 33 min; R60 = 95%
Excipient = aminopropyl silica 2 g–1 g NPX–SiNH2 #9 NPX–SiNH2 #10 2 g–2 g Physical mixture
Precipitation on slurry Precipitation on slurry Shaking
61% 50% 61%
Cx; d50/d90 = 93 ± 8/290 ± 19 μm; t90 = 50 ± 11 min; R60 = 92 ± 2% Cx; d50/d90 = 103 ± 17/330 ± 34 μm; t90 = 9 min; R60 = 100.1% t90 = 40 min; R60 = 93%
Excipient = silica NPX–UP #11
Precipitation on slurry
g–1 g–2 g–1 g–4 g–1
g g g g g
2 g–1 g
3.1. Crystallinity Whatever the excipient or the procedure (precipitation on slurry standard or fast, or dry mixing), naproxen was recovered in a crystalline form without noticeable modification of the X-ray diffraction pattern. Fig. 2 reports patterns obtained for mannitol-based formulations and of raw unprocessed materials. Naproxen is not known for polymorphism contrary to mannitol that exhibits three forms (namely α, β, and δ). In this work, the raw mannitol is the δ form as confirmed by the X-ray pattern. Despite the β form being the stable form, mannitol did not undergo polymorphic conversion when contacted with acetone + CO2 + naproxen or when contacted with CO2 and naproxen under higher temperature (50 °C vs 27 °C) and pressure (18 MPa vs 10 MPa). Both mannitol and naproxen patterns in formulations reassembled to unprocessed compounds, so no solvent- or CO2- mediated conversion was obtained. It is well known that the conversion from one form to another can be induced by heat, friction, grinding, and tabletting, but for mannitol, the most efficient way for conversion is moisture [33]. When the drug was coprocessed with the other excipients that are amorphous — Duolite®, silica or aminopropyl silica-, peaks of naproxen were clearly visible indicating that the drug was mostly produced in a crystalline form.
75%
Cx; d50/d90 = 157 ± 23/481 ± 112 μm; t90 = 79 ± 5 min; R60 = 85 ± 1%
PSD since the maximum of the second population shifted from 600 to 300 μm. This could indicate either the formation of smaller NPX crystals or less particles agglomeration that is compatible with the role of a dispersing agent. The microscopic image of the mannitol formulation is given in Fig. 4c. The powder was more easily dispersed on the observation slide, and although large particles were still visible on the image, their width stood below 100 μm and they were less frequent than for single-processed naproxen. Hence both smaller particles and less agglomeration contributed to the shift of the PSD. A diminution of mean size and PSD width was also obtained by introducing faster CO2 in the vessel (run #4 and #5 vs run #2), or by increasing the amount of the excipient in the slurry (run #3). The microscopic images (Fig. 4 d to f) showed that the width of particles was impacted as well since most particles had a width below 40 μm. The faster introduction corresponded to 2–3 folds of the normal rate, i.e. an introduction completed in 5–6 min instead of 12–15 min, meaning that more antisolvent per unit of time was introduced and dispersed within the solution by the vigorous stirring. Literature reports as well smaller sizes produced by increasing introduction rate [34,29,17], and it was postulated that higher nucleation rate was promoted by such conditions. 3.3. Particle sizes of Duolite and silica formulations
3.2. Particle sizes of mannitol-based formulations Fig. 3 compares first the particle size distribution (PSD) of raw NPX, NPX single processed (run #1) and NPX–mannitol processed by the dry route (run #6), e.g. materials were contacted without acetone in pressurized CO2. Since the medium for the analysis was water that dissolved mannitol, the PSD gave the distribution of naproxen only. The dry route yielded to a PSD very closed to that of the raw naproxen, which was also evidenced by microscopy (Fig. 4b); in this picture, the large colorless particles are of mannitol. The lack of any shift indicates that if some amount of NPX was solubilised by supercritical CO2, it was not enough to significantly affect the population size. Conversely, the precipitation induced by CO2 shifted the distribution to larger sizes, with d50 and d90 values of 118 and 693 μm, respectively, higher than the 20 and 242 μm of the unprocessed naproxen. The presence of mannitol as particles in suspension during the process (run #2) tends to compress the
Contrary to mannitol, Duolite® and silicas are insoluble in the analysis medium, hence the measured size distribution accounts for the two components of the formulation (Fig. 5). For the SiO2 excipient of 5 μm mean size, the PSD analysis evidenced clearly a small sized population in the 1–10 μm range that was the silica and a larger population with a maximum at 300 μm attributable to naproxen. Microscopic images (Fig. 5) evidenced as well the presence of free silica spheres and of naproxen crystals usually covered with silica particles. Such silica-covered-crystals matched the griseofulvine needles prepared by Thakur et al. [20] with the same GAS technique and our own results on tolbutamide [21] for which a bimodal distribution was measured as well. In case of the 0–100 μm aminopropyl silica, the NPX and SiNH2 populations overlapped (run #9) but the first maximum fits with the excipient distribution so that the second shoulder at 200 μm was thus
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# 6 (dry route) #2 #4 #3 #5 MNol raw NPX raw
Fig. 2. Powder X-ray diffraction patterns of naproxen–mannitol formulations produced by CO2 antisolvent precipitation on slurry and by dry contact. Experiments identified in Table 2.
attributed to NPX. The microscopic image (Fig. 5) allowed for making distinction between the round-shape excipient and the bright elongated naproxen and showed the presence of naproxen crystals longer than particles of excipient. The two maxima were better separated when the initial amount of excipient was doubled in the preparation, i.e. when a lower content of naproxen was recovered in the produced formulation (run #10). Less naproxen and more silica were also visible by microscopy (not shown). Duolite-based formulations showed peculiar behavior since PSD profiles evolved rapidly and fit after 6–12 min of analysis with the pure Duolite® distribution. Meanwhile, the X-ray patterns, the NPX
dosage and the microscopy images revealed without doubt the presence of Naproxen in formulations. Therefore, either Duolite and NPX particles had similar sizes, or the NPX particles dissolved quickly in water. Microscopy evidenced the presence of some large naproxen crystals of length around 300 μm. Duolite was the excipient that exhibited the largest PSD with a significant presence of particles above 150 μm that could screen the largest population of naproxen particles. Hence, the similar size was a probable scenario, although the fast dissolution cannot be completely discarded with regard to the dissolution study results. In terms of naproxen particle size in formulations produced with the same 2:1 NPX: excipient ratio, SiNH2 and Duolite provided smaller NPX
Fig. 3. Particle size distribution (in volume %) of mannitol-based formulations and comparison with unprocessed naproxen.
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a NPX:MNol 2g:0g
b NPX:MNol 1g:1g dry route
c NPX:MNol 2g:1g
d NPX:MNol 2g:1g, fast introduction
e NPX:MNol 2g:2g
f NPX:MNol 2g:4g, fast introduction
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Fig. 4. Microscopy images of naproxen (a) precipitated alone (NPX #1), (b) mixed by dry route with mannitol (NPX–MNol #6), and precipitated on mannitol slurry: (c) NPX–MNol #2, (d) NPX–MNol #4, (e) NPX–MNol #3, (f) NPX–MNol #5. Scale bar = 100 μm.
sizes than SiO2 and mannitol since the maximum of the secondary population was below 200 μm. 3.4. Dissolution studies Dissolution profiles of mannitol-based formulations produced by CO2-precipitation on slurry or dry contact were compared to those of unprocessed and single processed NPX (Fig. 6). The effect of the excipient is shown in Fig. 7 as well. For clarity, reproducibility bars are not displayed in the curves but deviations in characteristic parameters are reported in Table 2. Two characteristic parameters were selected: t90, the time corresponding to dissolution of NPX of 90% and R60 the percentage of dissolution at 60 min that is the duration of typical dissolution experiments. Unprocessed naproxen characteristics were 111 ± 24 min and 81 ± 4% for τ90 and R60, respectively. It is worth noting that 50% of NPX is dissolved in 9 ± 4 min. As general comment, it can be seen that all prepared formulations exhibited an increased dissolution rate compared to the unprocessed naproxen or single-processed one, the latter being the slowest sample to dissolve. The main possibilities for improving dissolution under constant hydrodynamic conditions are to decrease the particle size, optimizing the wetting characteristics of the compound surface or improving the apparent solubility of the
drug, that is by preparing nanosuspensions, micronization, modification of crystal habit, polymorphism, complexation, drug dispersion in carriers, formation of salts… [7]. Unprocessed naproxen might exhibit the smallest size (see microscopy image) but it was prone to agglomerate as indicated by a d90 around 240 μm. Hence, despite its advantageous size, it dissolved slower than all excipient-based formulations. Within formulations, naproxen particles themselves were not small (significant population in the range of 200 to 480 μm) and they were produced dominantly as crystals, two characteristics that do not help the dissolution. Therefore the observed enhanced dissolution of the formulations could be attributed to better wetting characteristics and/or interactions thanks to excipients. In case of mannitol-based formulations, the improvement was specially emphasized by a fast introduction of CO2 and a higher amount of mannitol in the initial slurry. Higher initial amount of MNol produced higher amount in formulations as well. Comparing kinetics of samples that contained around 73% of NPX, i.e. run #2, run #4 and a physical mixture of NPX and MNol obtained by hand-shaking the ingredients (Fig. 6a), it can be seen that the formulation #4 exhibited a faster dissolution rate. As seen in Table 2, the dry-route showed a significant improvement as well. In other words, the CO2 processing could improve the dissolution rate of NPX compared to a physical mixing of mannitol and naproxen.
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Fig. 5. Effect of excipient on the formulation sizes and microscopy images of the CO2-produced formulations. In green = no excipient (NPX #1); blue = raw Duolite or SiNH2; red = CO2produced formulations.
The behavior was slightly different when dissolution kinetics were monitored in buffered aqueous media and/or with the flowthrough method (Fig. 6b). All kinetics were faster, i.e. even the unprocessed NPX was completely dissolved in 40 min (effect of the buffer) and the trend between samples was not the same. For instance, a physical mixing of NPX and mannitol did not improve the NPX dissolution whereas the CO2 -treatment improved it, as noticed previously. Regarding the effect of the excipient measured for a given initial NPX: excipient ratio of 2:1 (Fig. 7), Duolite® and SiNH2 provided the faster dissolution whereas formulation of mannitol and SiO2 behaves similarly. More than the τ90 and the R60 that were in the same range, the excipient influenced the initial burst of the dissolution. According to PSD shown in Fig. 4, Duolite® and SiNH2 gave the more homogenous powder sizes since excipients and NPX were of similar range. Moreover,
naproxen can specifically interact with those two excipients through acid-base interactions in case of SiNH2 or ionic interactions with the ammonium and benzene functionalities of the Duolite® resin, interactions that can improve dissolution as with cyclodextrine [35]. The processing of NPX by precipitation on Duolite slurry (run #7, 70 wt.% NPX), by the dry mixing route (run #8, 46 wt.% NPX) or by mixing the materials by hand-shaking (70 wt.% NPX) gave the same dissolution curves, e.g. the processing by CO2 techniques did not improve the product properties. Similar behavior was observed for the SiNH2 samples prepared by hand-shaking and precipitation on slurry (run #9) at a final content of 60 wt.% NPX. When conditions of preparations provided a higher content of the excipient (run #10 vs run #9), the kinetic of dissolution was faster. Hence, for excipients susceptible to interact with naproxen, there is no benefit of the CO2-treatment since a physical mixture is sufficient to improve the drug dissolution rate.
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disappointing since most dissolution rates were of the same range, except for mannitol whose CO2-treatment improved the dissolution kinetics better than a physical mixing. The beneficial effect of this excipient was obtained as well by dry mixing under high pressure of CO2 without any solvent. The experimental set has proven the concept of CO2-induced precipitation of a drug on a slurry and has highlighted the benefit of the CO2 processing in case of the excipient mannitol. It is expected that the method could be improved by changing the operational conditions of GAS in order to decrease the NPX particle sizes and/or processing a component that dissolves slower than NPX in aqueous medium to emphasize differences with physical mixtures. Understanding the interplay between the drug precipitation and the excipient content is also a direction for future works.
References
Fig. 6. Dissolution profiles monitored by (a) the USP paddle method, of mannitol-based formulations (runs #2, #3, #4) compared to unprocessed naproxen, NPX precipitated alone (NPX #1) and a physical mixture of NPX and MNol at 74 wt.% of NPX; (b) dissolution profiles of unprocessed NPX, a physical mixture at 50 wt.% NPX and NPX–MNol #5 monitored by a flow-through cell in buffered medium.
4. Conclusions This work focused on screening the impact of various excipients and/or procedure of a new method that consists in a CO2-induced precipitation of a drug on a slurry. The expectations were that the presence of particulate materials in the initial solution might improve the final characteristics of the products in terms of size and of drug dissolution kinetics. Results showed that naproxen was always precipitated in a crystalline form with a size that was smaller than in absence of the excipient. The overall sizes of formulations were standing below 330 μm for the d90 values except for SiO2 and mannitol in standard conditions that exhibited several wider and larger crystals of naproxen than the SiNH2 or Duolite preparations. Most formulations exhibited an increase of the naproxen dissolution rate compared to the unprocessed drug, and that despite higher crystal sizes. Hence the beneficial role of excipients attributable to enhanced wetting characteristics and/or interactions was clearly demonstrated. Compared to physical mixtures obtained by hand shaking, the benefit of the CO2-treatment was somehow
Fig. 7. Effect of excipients on the dissolution profiles of formulations prepared with initial NPX:excipient ratio of 2:1 (runs #2–#7–#9–#11); comparison with unprocessed naproxen.
[1] K. Meyer, I. Zimmermann, Effect of glidants in binary powder mixtures, Powder Technol. 139 (2004) 40. [2] A. Vasilenko, B. Glasser, F. Muzzio, Shear and flow behavior of pharmaceutical blends — method comparison study, Powder Technol. 208 (2011) 628. [3] H. Takeuchi, S. Nagira, S. Tanimura, H. Yamamoto, Y. Kawashima, Tabletting of solid dispersion particles consisting of indomethacin and porous silica particles, Chem. Pharm. Bull. 53 (2005) 487. [4] K. Kho, K. Hadinoto, Effects of excipient formulation on the morphology and aqueous re-dispersibility of dry-powder silica nano-aggregates, Colloids Surf. A Physicochem. Eng. Asp. 359 (2010) 71–81. [5] N. Rabbani, P. Seville, The influence of formulation components on the aerosolisation properties of spray-dried powders, J. Control. Release 110 (2005) 130–140. [6] The Biopharmaceutics Classification System (BCS) guidance, http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco. [7] C. Leuner, J. Dressman, Improving drug solubility for oral delivery using solid dispersions, Eur. J. Pharm. Biopharm. 50 (2000) 47–60. [8] J. Andersson, J. Rosenholm, S. Areva, M. Lindén, Influences of material characteristics on ibuprofen drug loading and release profiles from ordered micro- and mesoporous silica matrices, Chem. Mater. 16–21 (2004) 4160–4167. [9] M. Mehanna, A. Motawaa, M. Samaha, Tadalafil inclusion in microporous silica as effective dissolution enhancer: optimization of loading procedure and molecular state characterization, J. Pharm. Sci. 100 (2011) 1805–1818. [10] P. Subra-Paternault, A. Vega-Gonzalez, Ch Roy, Encapsulation assistée par fluides supercritiques, Chapter of the book “Microencapsulation”, Coordinators: Vandamme, Poncelet, Subra, Edt. Lavoisier, 2007, ISBN 978-2-7430-0976-2 (in French). [11] T. Yasuji, H. Takeuchi, Y. Kawashima, Particle design of poorly water-soluble drug substances using supercritical fluid technologies, Adv. Drug Deliv. Rev. 60 (3) (2008) 388–398. [12] V. Majerik, G. Charbit, E. Badens, G. Horváth, L. Szokonya, N. Bosc, E. Teillaud, Bioavailability enhancement of an active substance by supercritical antisolvent precipitation, J. Supercrit. Fluids 40 (2007) 101–110. [13] S. Diankov, D. Barth, A. Vega-Gonzalez, I. Pentchev, P. Subra-Paternault, Impregnation isotherms of hydroxybenzoic acid on PMMA in supercritical carbon dioxide, J. Supercrit. Fluids 41 (2007) 164–172. [14] A.R. Duarte, A.-L. Simplicio, A. Vega-González, P. Subra-Paternault, P. Coimbra, M.H. Gil, H. de Sousa, C. Duarte, Impregnation of an intraocular lens for ophthalmic drug delivery, Curr. Drug Deliv. 5 (2008) 102–107. [15] H. Miura, M. Kanebako, H. Shirai, H. Nakao, T. Inagi, K. Terada, Enhancement of dissolution rate and oral absorption of a poorly water-soluble drug, K-832, by adsorption onto porous silica using supercritical carbon dioxide, Eur. J. Pharm. Biopharm. 76 (2010) 215. [16] J. Kluge, F. Fusaro, G. Muhrer, R. Thakur, M. Mazzotti, Rational design of drugpolymer co-formulations by CO2 anti-solvent precipitation, J. Supercrit. Fluids 48 (2) (2009) 176–182. [17] B. DeGioannis, P. Jestin, P. Subra, Morphology and growth control of griseofulvin recrystallized by compressed carbon dioxide as antisolvent, J. Cryst. Growth 262 (2004) 519–526. [18] C. Roy, D. Vrel, A. Vega-González, P. Jestin, S. Laugier, P. Subra-Paternault, Effect of CO2-antisolvent techniques on size distribution and crystal lattice of theophylline, J. Supercrit. Fluids 57 (3) (2011) 267–277. [19] P. Varughese, J. Li, D. Winstead, Supercritical antisolvent processing of γ-indomethacin: effects of solvent, concentration, pressure and temperature on SAS processed indomethacin, Powder Technol. 201 (2010) 64–69. [20] R. Thakur, E. Hudgins, E. Goncalves, G. Muhrer, Particle size and bulk powder flow control by supercritical antisolvent precipitation, Ind. Eng. Chem. Res. 48 (2009) 5302–5309. [21] P. Subra-Paternault, D. Vrel, C. Roy, Coprecipitation on slurry to prepare drugoxide-polymer formulations by supercritical antisolvent, J. Supercrit. Fluids 63 (2012) 69–80. [22] J.W. Mullin, Crystallization 3rd edition, in: Butterworth-Heinemann (Ed.), Butterworth-Heinemann, Great Britain, ISBN: 0 7506 1129 4, 1993, pp. 193–238. [23] In: Rowe, et al., (Eds.), Handbook of Pharmaceutical Excipients, 7th ed., Pharmaceutical Press, London, 2012, p. 479.
88
P. Subra-Paternault et al. / Powder Technology 255 (2014) 80–88
[24] B. Albertini, N. Passerini, M. Gonzalez-Rodrıguez, B. Perissutti, Lorenzo Rodriguez, Effect of aerosil® on the properties of lipid controlled release microparticles, J. Controlled Release 100 (2004) 233–246. [25] Rohm and Haas Data Sheet, DuoliteTM API43/I093, http://www.rohmhaas.com/ ionexchange/pharmaceuticals/2006. [26] M. Muntó, N. Ventosa, Sa. Sala, J. Veciana, Solubility behaviors of ibuprofen and naproxen drugs in liquid “CO2–organic solvent” mixtures, J. Supercrit. Fluids 47 (2008) 147–153. [27] S. Ting, S. Macnaughton, D. Tomasko, N. Foster, Solubility of naproxen in supercritical carbon dioxide with and without cosolvent, Ind. Eng. Chem. Res. 32 (1993) 1471–1481. [28] Z. Liu, D. Li, G. Yang, B. Han, Solubility of hydroxybenzoic acid isomers in ethyl acetate expanded by CO2, J. Supercrit. Fluids 18 (2000) 111–119. [29] Z. Liu, J. Wang, L. Song, G. Yang, B. Han, Study on the phase behavior of cholesterol– acetone–CO2 system and recrystallization of cholesterol by antisolvent CO2, J. Supercrit. Fluids 24 (2002) 1–6. [30] T. Rogers, I. Gillespie, J. Hitt, K. Fransen, C. Crowl, C. Tucker, G. Kupperblatt, J. Becker, D. Wilson, C. Todd, C. Broomall, J. Evans, J. Elder, Development and characterization
[31]
[32]
[33]
[34]
[35]
of a scalable controlled precipitation process to enhance the dissolution of poorly water-soluble drugs, Pharm. Res. 21 (2004) 2048. D. D'Arcy, B. Liu, O. Corrigan, Investigating the effect of solubility and density gradients on local hydrodynamics and drug dissolution in the USP 4 dissolution apparatus, Intern. J. Pharm. 419 (1–2) (2011) 175. F. Fusaro, M. Ha1nchen, M. Mazzotti, G. Muhrer, B. Subramaniam, Dense gas antisolvent precipitation: a comparative investigation of the GAS and PCA techniques, Ind. Eng. Chem. Res. 44 (2005) 1502–1509. T. Yoshinari, R. Forbes, P. York, Y. Kawashima, Moisture induced polymorphic transition of mannitol and its morphological transformation, Intern. J. Pharmaceutics 247 (2002) 69–77. G. Muhrer, U. Meier, F. Fusaro, S. Albano, M. Mazzotti, Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble drug: generation of drug microparticles and drug–polymer solid dispersions, Intern. J. Pharmaceutics 308 (2006) 69–83. F. Veiga, J. Teixeira-Dias, F. Kedzierewicz, A. Sousa, P. Maincent, Inclusion complexation of tolbutamide with β-cyclodextrin and hydroxypropyl- β-cyclodextrin, Intern. J. Pharmaceutics 129 (1996) 63–71.
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Powder Technology journal homepage: www.elsevier.com/locate/powtec
Preparation of naproxen–excipient formulations by CO2 precipitation on a slurry P. Subra-Paternault a,⁎, P. Gueroult b, D. Larrouture b, S. Massip c, M. Marchivie c a b c
CBMN — UMR 5248, Université Bordeaux 1 — IPB, Bât 14, Allée Geoffroy Saint Hilaire, 33600 Pessac, France Laboratoire de Technologie Pharmaceutique Industrielle, UFR Pharmacie, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France Laboratoire de Pharmacochimie, CNRS FRE 3396 UFR Pharmacie, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
a r t i c l e
i n f o
Available online 18 September 2013 Keywords: Formulation Crystallization Supercritical CO2 Mannitol Silica Naproxen
a b s t r a c t The work focused on screening the impact of various excipients and/or procedure in a new method that consists in a CO2-induced precipitation of a drug on a slurry. Naproxen (NPX) is a drug whose bioavailability could be improved by formulation with hydrophilic excipients. The investigated excipients were of various type, size and porosity, i.e. mannitol, silicas (SiO2 and SIO2 aminopropyl) and an anion exchange resin Duolite. The precipitation process used compressed CO2 as antisolvent for NPX and acetone as solvent to dissolve NPX and to suspend the excipient particles. Naproxen precipitated as crystals with a size distribution influenced by the NPX:excipient ratio for mannitol-based formulations. For other excipient co-precipitates, the overall size distributions were in the same range and below 330 μm except for the 5 μm silica. Due to the hydrophilic nature of the excipients, most formulations yielded an increased drug dissolution rate. Compared to physical mixtures, the benefit of the CO2 treatment was demonstrated in case of the excipient mannitol. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The use of excipients for manufacturing pharmaceutical products is a common practice of pharmacotechny. A challenge is to avoid the agglomeration of the active molecules in order to maintain the formulation uniformity. Besides improving the powder flowability, excipients can be used as diluent, binder, disintegrating, dispersing, gliding, lubricant agent [1–5]. One main development in pharmacy is to increase the bioavailability of compounds belonging to BCS Class II and Class III (Biopharmaceutics Classification System [6]), and specially of active pharmaceutical ingredient (API) whose bioavailability is restricted by a low solubility in biological fluids. The improvement can be realized by modifying the API characteristics like reducing the particle size or altering the crystal habit, or by adding a water-compatible ingredient which can complex or entrap the drug (surfactants, resins…) [7]. A particular way consists of using porous structures in which the drug could penetrate, as in the case of mesoporous silica that can take up to 40 wt.% of Ibuprofen [8]. The API is often dispersed in an amorphous form, which, combined with a better wettability of the silica-API structure in comparison with the API alone, leads generally to an increase of the API dissolution rate [9]. In pharmaceutical industry, the obtaining of active molecules in the form of powder is dominated by operations carried out in solution as crystallization, precipitation or synthesis. Meanwhile, new perspectives of API micronization or formulation are offered by using supercritical ⁎ Corresponding author. Tel.: +33 5 40 00 68 32. E-mail address: [email protected] (P. Subra-Paternault). 0032-5910/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.powtec.2013.09.012
fluids and mainly CO2 to partially or totally replace solvents [10–12]. Totally avoiding the solvents in the preparation of API formulations is difficult or at least it is restricted to few molecules soluble enough in supercritical CO2 to envisage sorption in porous carriers [13–15]. So far, many molecules are micronized by using CO2 as an antisolvent, a process in which CO2 is added to an initial solution to decrease the solubility of the molecule in the newly CO2 -solvent mixture and to provoke therefore the molecule precipitation [16–19]. On the same principle, this work develops the coupling of precipitation and in-situ formulation by adding the excipient as solid particles to the initial solution. Therefore, the process corresponds to a precipitation on slurry. It is worthwhile noting that literature reports many examples of API and polymer coprecipitation, but precipitation on suspension is rare. Developed initially by Thakur et al with silica as additive and griseofulvine as drug [20], we extended the concept to the more complex formulation of API + polymer + silica [21]. One can expect for the excipient to act, at a minimum as a deagglomerating agent for the API particles or as a more active carrier if API molecules are physically sorbed or entrapped when porous structures are selected. But presence of solid particles in the precipitation medium can also impact the precipitation behavior of the drug, since any substances other than the material to precipitate may act as an impurity and therefore possibly affect the nucleation and growth behaviors [22]. In this work, the selected API is naproxen, a non-steroidal antiinflammatory compound whose bioavailability could be improved by the use of hydrophilic excipients. The selected excipients are nonporous polyol (mannitol), two silicas of different porosity, size and functionality (SiO2 and SiO2 aminopropyl) and a granular Duolite® resin.
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Mannitol is widely used in pharmaceutical formulations due to its Generally Recognized as Safe (GRAS) status. It is typically used as bulking agent due to its high aqueous solubility, as diluent in rapidly dispersing oral dosage forms or as a carrier in dry powder inhalers [23]. Nanoporous silicas with controlled three-dimensional silicate structure (Sylysia in [15]) or nanometric size (Aerosil in [24]) are usually employed for enhanced bioavailability formulations. For availability and to avoid manipulating nanoparticles, we have selected silica particles larger than 5 μm that are typically used in chromatographic applications. Duolite® is a crosslinked water-insoluble anion exchange resin suitable for pharmaceutical applications either as an active ingredient or as a carrier for anionic drugs [25]. Derived from a copolymer of styrene and divinylbenzene, this resin offers complex interactions with naproxen via the benzene and ammonium functionalities. Regarding CO2 processing, pure naproxen has been precipitated from acetone [26] thanks to the solubility behavior in CO2 + acetone mixture [27]. Accordingly, the formulation process was carried out with acetone as initial liquor, under mild conditions of temperature (27 °C) and pressure (10 MPa). A low temperature process was selected to promote lowenergy conditions and because of the lower solubility of compounds in pure solvent or CO2-expanded solvent [28,29]; otherwise, CO2 might be a too weak antisolvent to induce a significant precipitation. All excipients were insoluble in acetone, so the initial liquor contained dissolved naproxen and the excipient particles that were maintained in suspension by a stirrer. The produced formulations were characterized for their crystallinity, particle size distribution, naproxen content and dissolution kinetics. For comparison purposes, CO2 essays without solvent were performed under conditions of higher pressure and temperature to promote naproxen solubilization. The goal of this dry route was also to realize an intimate mixing between the two powders.
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composition of the CO2-acetone mixture is given by the experimental curve displayed in Fig. 1 as well. By getting enriched in CO2, the liquid phase attained a composition in which the naproxen was not soluble anymore and thus precipitated. CO2 was added until a pressure higher than the mixture critical pressure was obtained, i.e. 10 MPa. A flux of fresh CO2 was next maintained through the vessel for 60 min in order to dry the particles while the vessel was heated to 36 °C to help at the solvent removal. After depressurization, the product was collected, weighed and characterized. In dry experiments carried out without organic solvent, NPX and excipient powders were introduced in the vessel and CO2 added at 57 °C up to 18 MPa to promote solubilization of naproxen. Ingredients and CO2 were kept in contact for 2 h under a stirring of 500 rpm. 2.3. Powder characterization 2.3.1. Morphology and particle size distribution (PSD) Morphology was observed par optical microscopy (Olympus BX51, model BX51TF, magnification ×10) and recorded by a ColorView UCMAD3 camera. Size distribution was measured by laser diffraction using a MasterSizer 2000 (Malvern) equipped with a low volume circulation device and SDS 0.3% as dispersion medium. Measurements were recorded every 5 min during 30 min. Since mannitol is highly soluble in water, the PSDs of mannitol-based formulations reflect only the naproxen sizes. 2.3.2. Crystallinity (XRD) Crystallinity was assessed by X-ray diffraction (XRD) of samples deposited on a stainless steel or silicium holder, using a D5005 Siemens diffractometer. Data were collected for 2θ angles of 3–40°, with a step size of 0.02° at a scanning speed of 0.06°/min.
2. Materials and methods 2.1. Materials Naproxen (NPX, 98% purity) was purchased from Sigma-Aldrich. Acetone (ACE, 99.8% purity) and CO2 (99.5% industrial grade) came from VWR and Air Liquide (France), respectively. Various excipients were used: mannitol (Parteck® Delta M, gifted by Merck; crystalline tablets below 50 μm in length (MNol)); porous silica of 5 μm mean size (SiO2 UltiPrep300, Interchim, France; spherical particles, 300 Å of pore diameter (UP)); aminopropyl-functionalized silica (Sigma-Aldrich, particles of 40–63 μm, pores of 60 Å (Si-NH2)); Duolite® (Rohm and Haas, copolymer of styrene and divinylbenzene and a quaternary amine, coarse particles of 1–400 μm, amorphous (duol)). Chemical formulae and micrography of raw materials are given in Table 1. 2.2. Experimental set-up and procedure Experiments were carried out in a batch GAS apparatus schematized in Fig. 1. Details of the equipment can be found elsewhere [17]. Briefly, the precipitation unit is a 0.490 L vessel equipped with sapphire windows and pressure and temperature sensors. The vessel temperature is controlled by electric heating tape (Tset of 27 °C). A stirrer ended by a Rushton-type turbine plunges into the solution. The CO2 introduced by a Lewa pump is dispersed into the solution through the holes of the turbine. Additionally, the stirrer maintains the excipient particles in suspension (R of 500 rpm). A stainless steel filter (porosity 5 μm) overtopped by a membrane disk of 0.22 μm in porosity collects the produced particles at the vessel bottom. In a typical experiment, the suspension was prepared by first dissolving 2 g of naproxen in 45 ml of acetone (C ≈ 0.34 Csat) and adding 1 g, 2 g or 4 g of excipient. The suspension was sonicated for 15 min and poured into the vessel. The CO2 was progressively introduced, inducing an increase of the vessel pressure and the enrichment of the liquid phase in CO2 according to the liquid–vapor diagram given in Fig. 1. The evolution of the overall
2.3.3. Naproxen content in formulations The powder samples were dispersed in acetone and diluted for monitoring the drug content by spectroscopy (Spectrometer UVIKON XS, Secomam). Naproxen was detected at a wavelength of 332 nm. A calibration curve between 0.032 and 0.12 mg/ml of NPX in acetone was first built. 2.3.4. Dissolution Dissolution kinetics of produced powders were continuously monitored using the USP 2 paddle method according to [30] and the online monitoring developed for tolbutamide release [21]. The dissolution medium consisted of 900 ml of 0.3% SDS water maintained at 37.0 °C and 30 mg equivalent NPX was added to the medium stirred at 50 rpm by a paddle. The drug release was monitored continuously by UV at 332 nm (UVIKON XS, Secomam) thanks to a peristaltic Heildorph pump that allowed for circulating the bulk solution through the UV flow cell. Few samples were also analyzed by a flow-through apparatus [31]. The flow-through apparatus (Eur.Phar. 7) consisted of a 2 L -reservoir of dissolution medium and Sotax pump that delivered the dissolution medium through the sample cell (22.6 mm i.d.) at 19 ml/min. The flowthrough cell that contained 10 mg equivalent NPX was maintained at 37.0 °C. A spectrophotometer equipped with a UV-flow cell monitored the NPX content at 232 nm. The dissolution medium consisted of phosphate buffer at pH 6.7. 3. Results and discussion Conditions and product characteristics are given in Table 2. Conditions and API:excipient ratio were selected on the basis of preceding results with silica [21] or of particle generation upon operating conditions [17]. The work focused on screening the impact of various excipients and/or procedure on the physical and dissolution characteristics of powders prepared by this new method for which literature background is rare. It is well known that smaller particles exhibit faster dissolution rate because
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Table 1 Naproxen and excipients used for CO2 induced formulations from acetone. Duolite structure from [25]. Soluble in acetone
Soluble in water
Naproxen (NPX)
Formula
Aspect of raw materials
Yes
Low
Mannitol (MNol)
No
Yes
Aminopropyl silica (SiNH2)
No
No
Silica (SiO2)
No
No
Duolite®
No
No
of their increased surface area [7]. Naproxen, in other hand, is quite soluble in acetone–CO2 mixtures [28,29], hence is prone to precipitate with large size because of the low obtainable level of supersaturation [22]. Conditions of GAS process were therefore selected in view of favoring smaller sizes [32], i.e. a low temperature of 27 °C, a vigorous stirring of 500 rpm and a fast introduction rate around 0.6–0.8 MPa/min. Naproxen was first precipitated as a single species from acetone, i.e. with no suspended excipient. The drug was recovered with a yield of 50% that indicated a quite high solubility in the CO2 + acetone mixture. The powder was granular with agglomerates that clung to a spatula and that were difficult to disperse for the observation by microscopy. Naproxen particles appeared as bright elongated particles with length of several hundreds of micron (Fig. 4a); many particles were also large,
with widths around 100 μm up to 320 μm. When co-processed with excipient in the ratio of 2:1, the produced powders contained about 70% ± 5% of naproxen, which was higher than the expectations based on the 50% yield of precipitation of run #1. Hence, the presence of particulate material in the solution improved the precipitation yield, but was irrespective of the excipient type so it did not depend on potential interactions of the API with the particles. Moreover, the produced powders with excipients showed enhanced flowability when compared to the single-processed drug. Although no quantitative analysis of flowability was performed, visual inspection with naked eyes during the transfer of samples from the storage flask to the microscope slide provided a qualitative evaluation: powders with excipients clung less to the spatula and were more dispersable on slide than single-processed drug.
Fig. 1. Experimental CO2 set-up and CO2 + acetone phase diagram in which the evolution of the overall composition upon the CO2 introduction is shown. Symbols = experimental data of run #7; dotted lines = liquid–vapor phase diagram.
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Table 2 Conditions and characteristics of CO2-produced formulations. Precipitation on excipient slurry; Vacetone = 45 ml, T = 27 °C, R = 500 rpm, Pfinal = 10 MPa. Dry mixing: T = 57 °C, R = 500 rpm, Pfinal = 18 MPa, contact time = 2 h. Physical mixture: hand-shaking a mixture of unprocessed NPX and the excipient. API–Excipient = Initial amount of naproxen and excipient; %NPX = content of NPX in produced powder (wt.%); Cx = crystalline form of naproxen; d50/d90 = characteristic diameters of the particle size distribution. Dissolution kinetics: t90 = time corresponding to 90% of dissolution; R60 = % of dissolution at 60 min. Mixture #
API–excipient
Protocole
% NPX
Characteristics
Unprocessed NPX NPX #1
– 2g
– Pure NPX precipitation
100% 100%
Cx; d50/d90 = 20 ± 5/242 ± 33 μm; t90 = 112 ± 28 min; R60 = 80 ± 5% Cx; d50/d90 = 118 ± 16/693 ± 188 μm; t90 = 190 ± 13 min; R60 = 69 ± 2%
Excipient = Mannitol NPX–MNol #2 2 NPX–MNol #3 2 NPX–MNol #4 2 NPX–MNol #5 2 NPX–MNol #6 1 Physical mixture
Precipitation on slurry Precipitation on slurry Precipitation on slurry, faster CO2 introduction Precipitation on slurry, faster CO2 introduction Dry route Shaking
73% 48% 71% 38% 53% 75%
Cx; d50/d90 = 152 ± 23/445 ± 35 μm; t90 = 48 ± 4 min; R60 = 95 ± 2% Cx; d50/d90 = 68 ± 7/235 ± 33 μm; t90 = 15 ± 1 min; R60 = 98 ± 1% Cx; d50/d90 = 54 ± 2/203 ± 37 μm; t90 = 17 ± 7 min; R60 = 100 ± 1% Cx; d50/d90 = 66 ± 15/226 ± 23 μm; t90 = 15 ± 1 min; R60 = 98 ± 1% Cx; d50/d90 = 22 ± 3/220 ± 29 μm; t90 = 15 ± 1 min; R6o = 98 ± 1% t90 = 70 min; R60 = 89%
Excipient = Duolite® NPX–duol #7 2 g–1 g NPX–duol #8 1 g–1 g Physical mixture
Precipitation on slurry Dry route Shaking
70% 46% 70%
Cx; d50/d90 = 74 ± 4/223 ± 23 μm; t90 = 38 min; R60 = 94% Cx; d50/d90 = 73 ± 11/226 ± 22 μm; t90 = 42 min; R60 = 94% t90 = 33 min; R60 = 95%
Excipient = aminopropyl silica 2 g–1 g NPX–SiNH2 #9 NPX–SiNH2 #10 2 g–2 g Physical mixture
Precipitation on slurry Precipitation on slurry Shaking
61% 50% 61%
Cx; d50/d90 = 93 ± 8/290 ± 19 μm; t90 = 50 ± 11 min; R60 = 92 ± 2% Cx; d50/d90 = 103 ± 17/330 ± 34 μm; t90 = 9 min; R60 = 100.1% t90 = 40 min; R60 = 93%
Excipient = silica NPX–UP #11
Precipitation on slurry
g–1 g–2 g–1 g–4 g–1
g g g g g
2 g–1 g
3.1. Crystallinity Whatever the excipient or the procedure (precipitation on slurry standard or fast, or dry mixing), naproxen was recovered in a crystalline form without noticeable modification of the X-ray diffraction pattern. Fig. 2 reports patterns obtained for mannitol-based formulations and of raw unprocessed materials. Naproxen is not known for polymorphism contrary to mannitol that exhibits three forms (namely α, β, and δ). In this work, the raw mannitol is the δ form as confirmed by the X-ray pattern. Despite the β form being the stable form, mannitol did not undergo polymorphic conversion when contacted with acetone + CO2 + naproxen or when contacted with CO2 and naproxen under higher temperature (50 °C vs 27 °C) and pressure (18 MPa vs 10 MPa). Both mannitol and naproxen patterns in formulations reassembled to unprocessed compounds, so no solvent- or CO2- mediated conversion was obtained. It is well known that the conversion from one form to another can be induced by heat, friction, grinding, and tabletting, but for mannitol, the most efficient way for conversion is moisture [33]. When the drug was coprocessed with the other excipients that are amorphous — Duolite®, silica or aminopropyl silica-, peaks of naproxen were clearly visible indicating that the drug was mostly produced in a crystalline form.
75%
Cx; d50/d90 = 157 ± 23/481 ± 112 μm; t90 = 79 ± 5 min; R60 = 85 ± 1%
PSD since the maximum of the second population shifted from 600 to 300 μm. This could indicate either the formation of smaller NPX crystals or less particles agglomeration that is compatible with the role of a dispersing agent. The microscopic image of the mannitol formulation is given in Fig. 4c. The powder was more easily dispersed on the observation slide, and although large particles were still visible on the image, their width stood below 100 μm and they were less frequent than for single-processed naproxen. Hence both smaller particles and less agglomeration contributed to the shift of the PSD. A diminution of mean size and PSD width was also obtained by introducing faster CO2 in the vessel (run #4 and #5 vs run #2), or by increasing the amount of the excipient in the slurry (run #3). The microscopic images (Fig. 4 d to f) showed that the width of particles was impacted as well since most particles had a width below 40 μm. The faster introduction corresponded to 2–3 folds of the normal rate, i.e. an introduction completed in 5–6 min instead of 12–15 min, meaning that more antisolvent per unit of time was introduced and dispersed within the solution by the vigorous stirring. Literature reports as well smaller sizes produced by increasing introduction rate [34,29,17], and it was postulated that higher nucleation rate was promoted by such conditions. 3.3. Particle sizes of Duolite and silica formulations
3.2. Particle sizes of mannitol-based formulations Fig. 3 compares first the particle size distribution (PSD) of raw NPX, NPX single processed (run #1) and NPX–mannitol processed by the dry route (run #6), e.g. materials were contacted without acetone in pressurized CO2. Since the medium for the analysis was water that dissolved mannitol, the PSD gave the distribution of naproxen only. The dry route yielded to a PSD very closed to that of the raw naproxen, which was also evidenced by microscopy (Fig. 4b); in this picture, the large colorless particles are of mannitol. The lack of any shift indicates that if some amount of NPX was solubilised by supercritical CO2, it was not enough to significantly affect the population size. Conversely, the precipitation induced by CO2 shifted the distribution to larger sizes, with d50 and d90 values of 118 and 693 μm, respectively, higher than the 20 and 242 μm of the unprocessed naproxen. The presence of mannitol as particles in suspension during the process (run #2) tends to compress the
Contrary to mannitol, Duolite® and silicas are insoluble in the analysis medium, hence the measured size distribution accounts for the two components of the formulation (Fig. 5). For the SiO2 excipient of 5 μm mean size, the PSD analysis evidenced clearly a small sized population in the 1–10 μm range that was the silica and a larger population with a maximum at 300 μm attributable to naproxen. Microscopic images (Fig. 5) evidenced as well the presence of free silica spheres and of naproxen crystals usually covered with silica particles. Such silica-covered-crystals matched the griseofulvine needles prepared by Thakur et al. [20] with the same GAS technique and our own results on tolbutamide [21] for which a bimodal distribution was measured as well. In case of the 0–100 μm aminopropyl silica, the NPX and SiNH2 populations overlapped (run #9) but the first maximum fits with the excipient distribution so that the second shoulder at 200 μm was thus
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# 6 (dry route) #2 #4 #3 #5 MNol raw NPX raw
Fig. 2. Powder X-ray diffraction patterns of naproxen–mannitol formulations produced by CO2 antisolvent precipitation on slurry and by dry contact. Experiments identified in Table 2.
attributed to NPX. The microscopic image (Fig. 5) allowed for making distinction between the round-shape excipient and the bright elongated naproxen and showed the presence of naproxen crystals longer than particles of excipient. The two maxima were better separated when the initial amount of excipient was doubled in the preparation, i.e. when a lower content of naproxen was recovered in the produced formulation (run #10). Less naproxen and more silica were also visible by microscopy (not shown). Duolite-based formulations showed peculiar behavior since PSD profiles evolved rapidly and fit after 6–12 min of analysis with the pure Duolite® distribution. Meanwhile, the X-ray patterns, the NPX
dosage and the microscopy images revealed without doubt the presence of Naproxen in formulations. Therefore, either Duolite and NPX particles had similar sizes, or the NPX particles dissolved quickly in water. Microscopy evidenced the presence of some large naproxen crystals of length around 300 μm. Duolite was the excipient that exhibited the largest PSD with a significant presence of particles above 150 μm that could screen the largest population of naproxen particles. Hence, the similar size was a probable scenario, although the fast dissolution cannot be completely discarded with regard to the dissolution study results. In terms of naproxen particle size in formulations produced with the same 2:1 NPX: excipient ratio, SiNH2 and Duolite provided smaller NPX
Fig. 3. Particle size distribution (in volume %) of mannitol-based formulations and comparison with unprocessed naproxen.
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a NPX:MNol 2g:0g
b NPX:MNol 1g:1g dry route
c NPX:MNol 2g:1g
d NPX:MNol 2g:1g, fast introduction
e NPX:MNol 2g:2g
f NPX:MNol 2g:4g, fast introduction
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Fig. 4. Microscopy images of naproxen (a) precipitated alone (NPX #1), (b) mixed by dry route with mannitol (NPX–MNol #6), and precipitated on mannitol slurry: (c) NPX–MNol #2, (d) NPX–MNol #4, (e) NPX–MNol #3, (f) NPX–MNol #5. Scale bar = 100 μm.
sizes than SiO2 and mannitol since the maximum of the secondary population was below 200 μm. 3.4. Dissolution studies Dissolution profiles of mannitol-based formulations produced by CO2-precipitation on slurry or dry contact were compared to those of unprocessed and single processed NPX (Fig. 6). The effect of the excipient is shown in Fig. 7 as well. For clarity, reproducibility bars are not displayed in the curves but deviations in characteristic parameters are reported in Table 2. Two characteristic parameters were selected: t90, the time corresponding to dissolution of NPX of 90% and R60 the percentage of dissolution at 60 min that is the duration of typical dissolution experiments. Unprocessed naproxen characteristics were 111 ± 24 min and 81 ± 4% for τ90 and R60, respectively. It is worth noting that 50% of NPX is dissolved in 9 ± 4 min. As general comment, it can be seen that all prepared formulations exhibited an increased dissolution rate compared to the unprocessed naproxen or single-processed one, the latter being the slowest sample to dissolve. The main possibilities for improving dissolution under constant hydrodynamic conditions are to decrease the particle size, optimizing the wetting characteristics of the compound surface or improving the apparent solubility of the
drug, that is by preparing nanosuspensions, micronization, modification of crystal habit, polymorphism, complexation, drug dispersion in carriers, formation of salts… [7]. Unprocessed naproxen might exhibit the smallest size (see microscopy image) but it was prone to agglomerate as indicated by a d90 around 240 μm. Hence, despite its advantageous size, it dissolved slower than all excipient-based formulations. Within formulations, naproxen particles themselves were not small (significant population in the range of 200 to 480 μm) and they were produced dominantly as crystals, two characteristics that do not help the dissolution. Therefore the observed enhanced dissolution of the formulations could be attributed to better wetting characteristics and/or interactions thanks to excipients. In case of mannitol-based formulations, the improvement was specially emphasized by a fast introduction of CO2 and a higher amount of mannitol in the initial slurry. Higher initial amount of MNol produced higher amount in formulations as well. Comparing kinetics of samples that contained around 73% of NPX, i.e. run #2, run #4 and a physical mixture of NPX and MNol obtained by hand-shaking the ingredients (Fig. 6a), it can be seen that the formulation #4 exhibited a faster dissolution rate. As seen in Table 2, the dry-route showed a significant improvement as well. In other words, the CO2 processing could improve the dissolution rate of NPX compared to a physical mixing of mannitol and naproxen.
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Fig. 5. Effect of excipient on the formulation sizes and microscopy images of the CO2-produced formulations. In green = no excipient (NPX #1); blue = raw Duolite or SiNH2; red = CO2produced formulations.
The behavior was slightly different when dissolution kinetics were monitored in buffered aqueous media and/or with the flowthrough method (Fig. 6b). All kinetics were faster, i.e. even the unprocessed NPX was completely dissolved in 40 min (effect of the buffer) and the trend between samples was not the same. For instance, a physical mixing of NPX and mannitol did not improve the NPX dissolution whereas the CO2 -treatment improved it, as noticed previously. Regarding the effect of the excipient measured for a given initial NPX: excipient ratio of 2:1 (Fig. 7), Duolite® and SiNH2 provided the faster dissolution whereas formulation of mannitol and SiO2 behaves similarly. More than the τ90 and the R60 that were in the same range, the excipient influenced the initial burst of the dissolution. According to PSD shown in Fig. 4, Duolite® and SiNH2 gave the more homogenous powder sizes since excipients and NPX were of similar range. Moreover,
naproxen can specifically interact with those two excipients through acid-base interactions in case of SiNH2 or ionic interactions with the ammonium and benzene functionalities of the Duolite® resin, interactions that can improve dissolution as with cyclodextrine [35]. The processing of NPX by precipitation on Duolite slurry (run #7, 70 wt.% NPX), by the dry mixing route (run #8, 46 wt.% NPX) or by mixing the materials by hand-shaking (70 wt.% NPX) gave the same dissolution curves, e.g. the processing by CO2 techniques did not improve the product properties. Similar behavior was observed for the SiNH2 samples prepared by hand-shaking and precipitation on slurry (run #9) at a final content of 60 wt.% NPX. When conditions of preparations provided a higher content of the excipient (run #10 vs run #9), the kinetic of dissolution was faster. Hence, for excipients susceptible to interact with naproxen, there is no benefit of the CO2-treatment since a physical mixture is sufficient to improve the drug dissolution rate.
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disappointing since most dissolution rates were of the same range, except for mannitol whose CO2-treatment improved the dissolution kinetics better than a physical mixing. The beneficial effect of this excipient was obtained as well by dry mixing under high pressure of CO2 without any solvent. The experimental set has proven the concept of CO2-induced precipitation of a drug on a slurry and has highlighted the benefit of the CO2 processing in case of the excipient mannitol. It is expected that the method could be improved by changing the operational conditions of GAS in order to decrease the NPX particle sizes and/or processing a component that dissolves slower than NPX in aqueous medium to emphasize differences with physical mixtures. Understanding the interplay between the drug precipitation and the excipient content is also a direction for future works.
References
Fig. 6. Dissolution profiles monitored by (a) the USP paddle method, of mannitol-based formulations (runs #2, #3, #4) compared to unprocessed naproxen, NPX precipitated alone (NPX #1) and a physical mixture of NPX and MNol at 74 wt.% of NPX; (b) dissolution profiles of unprocessed NPX, a physical mixture at 50 wt.% NPX and NPX–MNol #5 monitored by a flow-through cell in buffered medium.
4. Conclusions This work focused on screening the impact of various excipients and/or procedure of a new method that consists in a CO2-induced precipitation of a drug on a slurry. The expectations were that the presence of particulate materials in the initial solution might improve the final characteristics of the products in terms of size and of drug dissolution kinetics. Results showed that naproxen was always precipitated in a crystalline form with a size that was smaller than in absence of the excipient. The overall sizes of formulations were standing below 330 μm for the d90 values except for SiO2 and mannitol in standard conditions that exhibited several wider and larger crystals of naproxen than the SiNH2 or Duolite preparations. Most formulations exhibited an increase of the naproxen dissolution rate compared to the unprocessed drug, and that despite higher crystal sizes. Hence the beneficial role of excipients attributable to enhanced wetting characteristics and/or interactions was clearly demonstrated. Compared to physical mixtures obtained by hand shaking, the benefit of the CO2-treatment was somehow
Fig. 7. Effect of excipients on the dissolution profiles of formulations prepared with initial NPX:excipient ratio of 2:1 (runs #2–#7–#9–#11); comparison with unprocessed naproxen.
[1] K. Meyer, I. Zimmermann, Effect of glidants in binary powder mixtures, Powder Technol. 139 (2004) 40. [2] A. Vasilenko, B. Glasser, F. Muzzio, Shear and flow behavior of pharmaceutical blends — method comparison study, Powder Technol. 208 (2011) 628. [3] H. Takeuchi, S. Nagira, S. Tanimura, H. Yamamoto, Y. Kawashima, Tabletting of solid dispersion particles consisting of indomethacin and porous silica particles, Chem. Pharm. Bull. 53 (2005) 487. [4] K. Kho, K. Hadinoto, Effects of excipient formulation on the morphology and aqueous re-dispersibility of dry-powder silica nano-aggregates, Colloids Surf. A Physicochem. Eng. Asp. 359 (2010) 71–81. [5] N. Rabbani, P. Seville, The influence of formulation components on the aerosolisation properties of spray-dried powders, J. Control. Release 110 (2005) 130–140. [6] The Biopharmaceutics Classification System (BCS) guidance, http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco. [7] C. Leuner, J. Dressman, Improving drug solubility for oral delivery using solid dispersions, Eur. J. Pharm. Biopharm. 50 (2000) 47–60. [8] J. Andersson, J. Rosenholm, S. Areva, M. Lindén, Influences of material characteristics on ibuprofen drug loading and release profiles from ordered micro- and mesoporous silica matrices, Chem. Mater. 16–21 (2004) 4160–4167. [9] M. Mehanna, A. Motawaa, M. Samaha, Tadalafil inclusion in microporous silica as effective dissolution enhancer: optimization of loading procedure and molecular state characterization, J. Pharm. Sci. 100 (2011) 1805–1818. [10] P. Subra-Paternault, A. Vega-Gonzalez, Ch Roy, Encapsulation assistée par fluides supercritiques, Chapter of the book “Microencapsulation”, Coordinators: Vandamme, Poncelet, Subra, Edt. Lavoisier, 2007, ISBN 978-2-7430-0976-2 (in French). [11] T. Yasuji, H. Takeuchi, Y. Kawashima, Particle design of poorly water-soluble drug substances using supercritical fluid technologies, Adv. Drug Deliv. Rev. 60 (3) (2008) 388–398. [12] V. Majerik, G. Charbit, E. Badens, G. Horváth, L. Szokonya, N. Bosc, E. Teillaud, Bioavailability enhancement of an active substance by supercritical antisolvent precipitation, J. Supercrit. Fluids 40 (2007) 101–110. [13] S. Diankov, D. Barth, A. Vega-Gonzalez, I. Pentchev, P. Subra-Paternault, Impregnation isotherms of hydroxybenzoic acid on PMMA in supercritical carbon dioxide, J. Supercrit. Fluids 41 (2007) 164–172. [14] A.R. Duarte, A.-L. Simplicio, A. Vega-González, P. Subra-Paternault, P. Coimbra, M.H. Gil, H. de Sousa, C. Duarte, Impregnation of an intraocular lens for ophthalmic drug delivery, Curr. Drug Deliv. 5 (2008) 102–107. [15] H. Miura, M. Kanebako, H. Shirai, H. Nakao, T. Inagi, K. Terada, Enhancement of dissolution rate and oral absorption of a poorly water-soluble drug, K-832, by adsorption onto porous silica using supercritical carbon dioxide, Eur. J. Pharm. Biopharm. 76 (2010) 215. [16] J. Kluge, F. Fusaro, G. Muhrer, R. Thakur, M. Mazzotti, Rational design of drugpolymer co-formulations by CO2 anti-solvent precipitation, J. Supercrit. Fluids 48 (2) (2009) 176–182. [17] B. DeGioannis, P. Jestin, P. Subra, Morphology and growth control of griseofulvin recrystallized by compressed carbon dioxide as antisolvent, J. Cryst. Growth 262 (2004) 519–526. [18] C. Roy, D. Vrel, A. Vega-González, P. Jestin, S. Laugier, P. Subra-Paternault, Effect of CO2-antisolvent techniques on size distribution and crystal lattice of theophylline, J. Supercrit. Fluids 57 (3) (2011) 267–277. [19] P. Varughese, J. Li, D. Winstead, Supercritical antisolvent processing of γ-indomethacin: effects of solvent, concentration, pressure and temperature on SAS processed indomethacin, Powder Technol. 201 (2010) 64–69. [20] R. Thakur, E. Hudgins, E. Goncalves, G. Muhrer, Particle size and bulk powder flow control by supercritical antisolvent precipitation, Ind. Eng. Chem. Res. 48 (2009) 5302–5309. [21] P. Subra-Paternault, D. Vrel, C. Roy, Coprecipitation on slurry to prepare drugoxide-polymer formulations by supercritical antisolvent, J. Supercrit. Fluids 63 (2012) 69–80. [22] J.W. Mullin, Crystallization 3rd edition, in: Butterworth-Heinemann (Ed.), Butterworth-Heinemann, Great Britain, ISBN: 0 7506 1129 4, 1993, pp. 193–238. [23] In: Rowe, et al., (Eds.), Handbook of Pharmaceutical Excipients, 7th ed., Pharmaceutical Press, London, 2012, p. 479.
88
P. Subra-Paternault et al. / Powder Technology 255 (2014) 80–88
[24] B. Albertini, N. Passerini, M. Gonzalez-Rodrıguez, B. Perissutti, Lorenzo Rodriguez, Effect of aerosil® on the properties of lipid controlled release microparticles, J. Controlled Release 100 (2004) 233–246. [25] Rohm and Haas Data Sheet, DuoliteTM API43/I093, http://www.rohmhaas.com/ ionexchange/pharmaceuticals/2006. [26] M. Muntó, N. Ventosa, Sa. Sala, J. Veciana, Solubility behaviors of ibuprofen and naproxen drugs in liquid “CO2–organic solvent” mixtures, J. Supercrit. Fluids 47 (2008) 147–153. [27] S. Ting, S. Macnaughton, D. Tomasko, N. Foster, Solubility of naproxen in supercritical carbon dioxide with and without cosolvent, Ind. Eng. Chem. Res. 32 (1993) 1471–1481. [28] Z. Liu, D. Li, G. Yang, B. Han, Solubility of hydroxybenzoic acid isomers in ethyl acetate expanded by CO2, J. Supercrit. Fluids 18 (2000) 111–119. [29] Z. Liu, J. Wang, L. Song, G. Yang, B. Han, Study on the phase behavior of cholesterol– acetone–CO2 system and recrystallization of cholesterol by antisolvent CO2, J. Supercrit. Fluids 24 (2002) 1–6. [30] T. Rogers, I. Gillespie, J. Hitt, K. Fransen, C. Crowl, C. Tucker, G. Kupperblatt, J. Becker, D. Wilson, C. Todd, C. Broomall, J. Evans, J. Elder, Development and characterization
[31]
[32]
[33]
[34]
[35]
of a scalable controlled precipitation process to enhance the dissolution of poorly water-soluble drugs, Pharm. Res. 21 (2004) 2048. D. D'Arcy, B. Liu, O. Corrigan, Investigating the effect of solubility and density gradients on local hydrodynamics and drug dissolution in the USP 4 dissolution apparatus, Intern. J. Pharm. 419 (1–2) (2011) 175. F. Fusaro, M. Ha1nchen, M. Mazzotti, G. Muhrer, B. Subramaniam, Dense gas antisolvent precipitation: a comparative investigation of the GAS and PCA techniques, Ind. Eng. Chem. Res. 44 (2005) 1502–1509. T. Yoshinari, R. Forbes, P. York, Y. Kawashima, Moisture induced polymorphic transition of mannitol and its morphological transformation, Intern. J. Pharmaceutics 247 (2002) 69–77. G. Muhrer, U. Meier, F. Fusaro, S. Albano, M. Mazzotti, Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble drug: generation of drug microparticles and drug–polymer solid dispersions, Intern. J. Pharmaceutics 308 (2006) 69–83. F. Veiga, J. Teixeira-Dias, F. Kedzierewicz, A. Sousa, P. Maincent, Inclusion complexation of tolbutamide with β-cyclodextrin and hydroxypropyl- β-cyclodextrin, Intern. J. Pharmaceutics 129 (1996) 63–71.