Precipitation and phase behavior of theophylline in solvent–supercritical CO2 mixtures

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Abstract

An experimental study of precipitation by CO2–antisolvent process has been performed with special attention to the role of phase behavior, spray regime and concentration in controlling morphology and dimensions of precipitates. Theophylline (THEO) was selected as model compound. Phase equilibria of solvent–CO2 and theophylline–solvent–CO2 systems were first investigated by a synthetic method, besides measurement of theophylline solubility in various solvents at atmospheric pressure. The solubility of theophylline in ethanol–CO2 (EtOH–CO2) and in ethanol–methylene chloride–CO2 (EtOH–DCM–CO2) mixtures was measured at 309.15 K and 10 MPa, based on the determination of the precipitation point. Besides confirmation of the antisolvent effect of CO2, the phase behavior study pointed the interest of an addition of methylene chloride to ethanol, since a significant enhancement of theophylline solubility was observed at atmospheric pressure and high pressure as well. Recrystallization of theophylline was successfully performed in a semi-continuous apparatus, provided that EtOH–DCM mixtures were used as dissolution media. The effect of pressure, temperature, theophylline concentration in the solution and solution flow rate were investigated. Plate-like aggregates were usually produced, with length ranging from 15 to 500 μm depending on experimental conditions. Conditions of pressure and temperature were selected to explore both single-phase or two-phases conditions. Depending on those conditions, we observed two different mixing mechanisms that largely influenced size and aggregation of precipitated particles. Particularly, we have shown that conditions near the critical region led to a production of slightly aggregated particles below 15 μm in length, with a precipitation yield of about 80%.

Introduction

The production of micro- and nano-particles with controlled characteristics is of great importance in several industrial fields. Supercritical fluids (SCF) based processes are gaining importance as alternatives to conventional liquids based processes. A promising SCF process is the supercritical antisolvent precipitation that has been already tested for several kinds of compounds [1], [2]. Although many applications have been proposed, studies on phase behaviors involved in antisolvent processes and their implications in product characteristics are scarce. Most of the work has been concentrated on the effects of various operating parameters on the product size and morphology, with experimental conditions usually settled above the critical mixture point for the binary solvent–CO2 system. In several cases, unsuccessful precipitations were reported, [3], [4], even when conditions were correctly selected on the basis of binary systems behavior. Such unsuccessful runs point out the necessity of considering the phase behavior of the ternary system formed by the solute, the solvent and the supercritical fluid.

Vapor–liquid phase equilibria for binary and ternary systems can be studied using a synthetic method. This method was recently proposed to investigate phase behavior of several ternary systems of interest for solute micronization [5], [6], [7], [8]. We already have settled a static equipment for describing LV phase-border curves [9] and measuring expansion of various liquids upon addition of carbon dioxide [10]. Considering a ternary system of solvent1 + solvent2 + CO2, the equipment allowed for determining pressures at which complete miscibility was obtained, and the two-phases or three-phases coexistence curves [11]. More recently, a static synthetic method was validated for determining the solubility of a solid in CO2 + solvent mixtures, in which CO2 was either antisolvent or co-solvent [8].

In this work, theophylline (THEO) was chosen as a model compound to progress in the understanding of fundamentals involved in recrystallization by CO2. At this stage, the aim was to gain insight at the role of phase behavior for controlling size of precipitates, rather than developing a new route for theophylline production. Theophylline is a methylxanthine derivative used for its bronchodilatory effects, but its low solubility in water (below 0.9 wt.% at 296 K [12], [13]) highly restricts its clinical applications. The drug also shows a narrow therapeutic range with a small difference between therapeutic benefits and toxicity effects and exhibits a dose-dependent pharmacokinetic [14], [15]. It is a drug with a short half-life, therefore, rapid release preparations are required to be administered in multiple daily doses, which may lead to poor patient compliance. In order to improve the drug action, various formulations of theophylline or derivatives with polymers were developed [15], including multiple w/o/w emulsions for either rapid, moderate or sustained delivery [16].

The use of supercritical techniques for formulation of theophylline was already reported. Solid dispersion with cellulose derivatives was produced by antisolvent precipitation [17], but no information was given for particle size, precipitation yield or phase equilibria. The two components were processed using a 1:1 mixture of methylene chloride/ethanol, since ethanol was the best solvent for theophylline and methylene chloride was the best for cellulose derivatives. A mixture of two solvents is frequently used when the precipitation is aimed at producing drug delivery devices [3], [18], since the polymer and the drug rarely exhibit similar solvation properties in the same solvent. Formulation of theophylline with hydrogenated palm oil (HPO) was also proposed using a PGSS-like (particles from gas saturated solutions) process [19]. Based on the expansion of the CO2–theophylline–HPO mixture, the process produced nearly spherical shaped particles of about 2–3 μm containing 0.5–3.5% (w/w) of theophylline.

In this work, the solubility of theophylline in CO2–ethanol and in CO2–ethanol–methylene chloride mixtures was determined by a static method. The solvent mixture was selected from the screening of theophylline dissolution in several organic solvents at atmospheric pressure, results that are also reported in this work. Then, precipitation of theophylline by a semi-continuous CO2–antisolvent process was performed. The influence of several process parameters on crystal size have been studied and analyzed in relation with the thermodynamic data.

Section snippets

Materials

Theophylline was purchased from Sigma (purity of 99%). The unprocessed theophylline had a rod morphology, with sizes ranging between 200 μm and 1 mm in length and a thickness between 40 and 100 μm.

Carbon dioxide (CO2, 99.5% purity) is supplied by Air Liquide. Organic solvents were purchased from Prolabo (France): methylene chloride (DCM), purity of 99.5%; absolute ethanol (EtOH), purity of 99.5%; dimethyl sulfoxide (DMSO), purity of 99.5%; ethyl acetate (AcOEt), purity of 99.5%; acetone (ACE),

Solubility of theophylline in pure solvents

The purpose of these dissolution tests was to screen the solvation ability of several solvents for theophylline in order to select a suitable medium for recrystallization by CO2–antisolvent process. Solvents were selected based on their polarity (indicated by the solubility parameter in Table 1) and their miscibility with CO2. Theophylline solubilities in various organic solvents and temperatures are reported in Table 2. The solubility in pure ethanol at 298.15 K agreed with data obtained by

Conclusions

Theophylline precipitation by the SAS process has been performed with special attention to the role of phase behavior, regime—formation of droplets or mixing of the streams—and concentration in controlling dimensions of the precipitates. The phase behavior study first pointed the interest of using mixtures of two solvents to modify both the solubility and the VLE behavior of the studied system. The addition of methylene chloride to ethanol indeed enhanced the solubility of theophylline in

Acknowledgements

C.-G. Laudani gratefully acknowledges the support of the Università degli Studi di Salerno, Italy, through a Faculty Scholarship. Authors thank P. Portes at LIMHP for SEM pictures.

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