International Journal of Pharmaceutics 383 (2010) 236–243Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Determination of poly(-caprolactone) solubility parameters: Application to solvent substitution in a microencapsulation process C. Bordes a,∗ , V. Fréville a , E. Ruffin b , P. Marote a , J.Y. Gauvrit a , S. Brianc ¸ on b , P. Lantéri a a b Université de Lyon, F-69622, Lyon, France; Université Lyon 1, Villeurbanne; LSA, UMR 5180, CNRS, CPE, 43 bd du 11 novembre, 69100 Villeurbanne, France Université de Lyon, F-69622, Lyon, France; Université Lyon 1, Villeurbanne; LAGEP, UMR 5007, CNRS, CPE, 43 bd du 11 novembre, 69100 Villeurbanne, France a r t i c l e i n f o a b s t r a c t The evolution of regulation on chemical substances (i.e. REACH regulation) calls for the progressive substitution of toxic chemicals in formulations when suitable alternatives have been identified. In this context, the method of Hansen solubility parameters was applied to identify an alternative solvent less toxic than methylene chloride used in a microencapsulation process. During the process based on a multiple emulsion (W/O/W) with solvent evaporation/extraction method, the solvent has to dissolve a polymer, poly(-caprolactone) (PCL), which forms a polymeric matrix encapsulating or entrapping a therapeutic protein as the solvent is extracted. Therefore the three partial solubility parameters of PCL have been determined by a group contribution method, swelling experiments and turbidimetric titration. The results obtained allowed us to find a solvent, anisole, able to solubilize PCL and to form a multiple emulsion with aqueous solutions. A feasibility test was conducted under standard operating conditions and allowed the production of PCL microspheres. © 2009 Elsevier B.V. All rights reserved. Article history: Received 7 July 2009 Received in revised form 4 September 2009 Accepted 11 September 2009 Available online 23 September 2009 Keywords: Hansen solubility parameters Solvent substitution Poly(-caprolactone) Microencapsulation Anisole 1. Introduction Solvents are essential products in many sectors of industry and everyday life. They are found in various fields such as detergents, agrochemicals, cosmetics, pharmaceuticals, paints, varnishes and inks. In recent years, regulations on solvents are more stringent because of their impact on the environment and health. The REACH directive (Registration, Evaluation and Authorization of Chemicals) requires manufacturers to prove the safety of the substances they use. Indeed, the impact of very few of the 100,000 chemicals used in everyday life have actually been evaluated on human health and environment. Accordingly, many formulations must be modified by replacing certain solvents by less toxic and more environmentally friendly ones. The substitution of one or more solvents in a formulation remains a complex problem. There are more or less empirical tools allowing the prediction of the solubility of a compound in a solvent (Modarresi et al., 2008). The most common method used by formulators and applied in this study is based on the Hansen solubility parameters (Hansen, 2007). In chemical engineering developments, thermodynamic models such as Universal Quasichemical Activity Coefficient (UNIQUAC) or Non-Random Two ∗ Corresponding author. Tel.: +33 4 72 44 85 61; fax: +33 4 72 44 83 19. E-mail address:
[email protected] (C. Bordes). 0378-5173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.09.023 Liquid (NRTL) models (Chen and Crafts, 2006) based on the concept of local composition or the Universal Functional Activity Coefficient (UNIFAC) predictive model (Gracin et al., 2002) using group contributions are more commonly used (Manifar and Rohani, 2005). Another approach consists in collecting experimental and theoretical molecular descriptors which are analyzed by using statistical techniques in order to obtain Quantitative Structure–Property Relationship (QSPR) models (Code et al., 2008; Tantishaiyakul et al., 2006; Yu et al., 2006) and/or solvent classifications (Chastrette et al., 1985; Gramatica et al., 1999; Katritzky et al., 2005; Xu and Redman-Furey, 2007). In this context, we are interested in the substitution of a solvent, methylene chloride (MC), used in a microencapsulation process for therapeutic proteins (Al Haushey et al., 2007). Indeed, MC belongs to the class of solvents whose use is subject to limitation by the European Pharmacopoeia, because of their inherent toxicity (Class 2) (European Pharmacopoeia, 2009). During the process, MC makes soluble a polymer (poly(-caprolactone) (PCL)) which forms a polymeric matrix encapsulating the protein as the organic solvent is extracted. PCL is a biodegradable polymer (an aliphatic polyester) obtained by ring opening polymerization of caprolactone (Fig. 1). PCL has a semi-crystalline structure and a glass transition temperature (Tg ) of −60 ◦ C. PCL easy crystallization explains its limited solubility in many solvents which are able to dissolve other amorphous polyester structures. The PCL degradation kinetics is very slow, making it suitable for slow release delivery systems with long term kinetics extending over periods exceeding 1 year (Sinha et al., 2004). Wang. Materials and methods 3. Their theory may explain the non-ideal character of polymer solutions. solvents in which a given molecule is soluble form a cloud of points corresponding in most cases to a sphere whose center point is the solute coordinates. The more a solvent is close to the solute in the “Hansen space”. It is then possible to compare the solubilizing power of solvents for a given solute by classifying according to their distance from the solute (the center of the sphere). All solvents and mixtures found in this volume are good solvents for the studied solute and the solvents outside are non-solvents. The total solubility parameter is then calculated by Eq. 2008). 1970.. 1991. Swelling tests of the polymer have to be performed at well-defined temperature and concentration.2. In the “Hansen space”. The determination of the solubility volume (or solubility sphere) is derived from visual observations. All other chemicals and solvents used were of analytical grade. In this study. 2007). The effectiveness of a non-tested solvent with well-known solubility parameters can be predicted by positioning it within or outside the solubility sphere. The solubility parameter of a substance was defined as the square root of the cohesion energy per unit volume. ıh = V (5) (2) where HM is the heat of mixing..5. 3.2. Determination of solubility parameters 3. Solubility parameters: theory Hildebrand introduced the concept of solubility parameter for non-polar compounds by noting that the vaporization enthalpy ( Hv ) reflects the amplitude of cohesion intermolecular forces in liquids (Hildebrand and Scott. Tables giving group contributions are available in the literature (Barton. Another approach to understand the solubility of a polymer was developed in the early 50s by Flory and Huggins (Flory. 2007) The experimental estimation of the solubility parameters of slightly volatile compounds can be done by several techniques: by swelling tests (Schenderlein et al. water has to be excluded from a standard set of test liquids because of its particular behavior in relation with its low molecular volume. with V the molar volume: ı= Hv − RT V 1/2 Poly(-caprolactone) (Mw = 14. ıp corresponds to Keesom forces occurring when two permanent dipoles are present (polar part) and ıh represents hydrogen bonding forces (hydrogen part).1. Fp the polar component and Eh the contribution of hydrogen bonding forces. Bordes et al.2.1. The experimental determination of solubility parameters generally requires the choice of reference solvents whose solubility parameters are known and well distributed in the “Hansen space”. The Flory–Huggins parameter 12 was included in the definition of the mixing enthalpy and can be related to the solubility parameters of two substances by the relation: 12 = VM 2 (ı1 − ı2 ) RT (4) . 2004).000) was purchased from Aldrich Chemical Company. Group contribution methods Polymer solubility parameters can be calculated by several methods involving group contributions as the methods of Van Krevelen (Hoy. a polar part and a hydrogen part) according to (Hansen. 1976) or more recently the method proposed by Stefanis and Panayiotou (2008). Experimental methods (Barton.. When 12 is less than 0. ıp = Hildebrand has shown that the solubility of two substances 1 and 2 will occur for a minimal mixing free energy i. 2008.000 and 65. Barton and Hansen recommend the selection of about 40 solvents belonging to different compound families (Barton. These methods are presented below. 1. 3. (3). Hansen suggested the splitting of the “global” Hildebrand solubility parameter into three parts derived from different types of cohesive forces (a disperse part.5 corresponds to a poor solvent. its very high ıh parameter and its tendency to self-associate or associate with other substances forming special structures. the better its affinity for this solute. swelling tests and turbidimetric titration were performed. 3. 1953). Hansen. we chose to determine the PCL Hansen solubility parameters through different techniques in order to obtain clear indications for substituting MC and to select a suitable alternative solvent belonging to the Class 3 of solvents with low toxic potential whose use is recommended by the European Pharmacopoeia. In this study. 2003) and by inverse gas chromatography (IGC) (Tian and Munk. 2007): 2 ı = (ı 2 + ı2 p + ıh ) d 1/2 where Fd is the dispersion component. / International Journal of Pharmaceutics 383 (2010) 236–243 237 where ı1 and ı2 are the solubility parameters of the solvent and the polymer respectively. In 1967. Hansen.2. ϕ1 and ϕ2 are the volume fractions of substances 1 and 2 respectively and VM is the volume of the mixture. 1950). by viscosity measurements (Wang. Sreekanth and Reddy. Van Krevelen approach is one of the most common methods in which each parameter can be estimated using the following equations (Van Krevelen and Hoftyzer. Van Krevelen and Hoftyzer. Poly(vinyl alcohol) (PVA) from Fluka was used as a stabilizer in the external phase in the microencapsulation process. Hansen solubility parameters define a three dimension “solubility space” in which all liquid or solid substances may be localized. when their solubility parameters will be identical or tend toward equality ı1 = ı2 : HM − VM ϕ1 ϕ2 (ı1 − ı2 ) 2 . 2. 1976): F i di F2 i pi V E i hi (1) ıd = V . 1991. Solvents which are closest to the center are those that are thermodynamically more likely to give a stable solution. 2004.e. Materials Fig. Swelling tests. by turbidimetric titration (Schenderlein et al. while a value higher than 0. The unit of solubility parameters in the SI unit system is (MPa)1/2 . (3) where ıd corresponds to the so-called London interaction resulting from the existence of induced dipoles as two molecules approach one another (disperse part). 3. According to Hansen (2007). Structure of poly(-caprolactone) (PCL). 1994.2.2.1. 2003). the solvent is generally considered as a good solvent for the polymer. Adamska et al.C. 1991). two non-solvents have to be chosen so that one (1) has a solubility parameter lower than the solvent (2) solubility parameter and the second (3) has a higher one. the polymer solubility parameter ıapp.7 ıh 8.000 (PCL14000) and 65. Turbidimetric titration. The radius Rs can be determined by different methods: by determining the maximum distance between the good solvent the furthest from the center and the sphere center (Eq. 2). 3. each partial solubility parameter is graphically obtained and corresponds to the intersection between the plotted regression line obtained from Eq. partially soluble (b) and non-soluble (c) (Fig. It is characterized by the three coordinates of its center ıdP .8 5.8 8. / International Journal of Pharmaceutics 383 (2010) 236–243 Table 1 PCL solubility parameters obtained by different methods.238 C.5 g/5 mL) PCL65000 (2.1 5.1 4.1. The microspheres were dedicated to the encapsulation of therapeutic proteins.0 5.0 ıp 4. (6) in comparison with the two other parameters. this calculation takes into account neither the molecular weight nor polymer concentration. ıpP = N ı S =1 pS N .6 17.2. A multiple emulsion W1 /O/W2 was then obtained by mixing the first emulsion with an external aqueous phase containing poly(vinyl alcohol) (PVA) as a stabilizer and isopropanol to extract MC.3 and are reported in Table 1.2 6. Results and discussion 4. ıhP (solubility parameters of the compound to solubilize) and by its radius Rs . The extraction of MC and evaporation of both solvents led to the formation of PCL microparticles which were then filtered. Hansen.2 3. This experimental method based on the Flory–Huggins theory allows the clarification of the solubility volume limits by studying several mixtures of solvents and nonsolvents (Suh and Clarke.3 < R < 7. 1991. a solution of MC and PCL (2 g of PCL in 5 mL of MC).5 g of PCL were introduced into sealed test tubes containing 5 mL of solvent.8 16. Swelling tests were also performed at the maximum concentration 2.4 7.p = ım.p is about the apparent Flory–Huggins parameter and is defined by the following equation: ıapp.4 7. 4.3 6.high (10) Vm.2.5 g of PCL in 5 mL used for the microencapsulation process and for two types of PCL with different molecular weight 14.5 g/5 mL) The distance D between a solvent (S) and the solute (P) in the “solubility space” is calculated by the following equation: D = (4(ıdS − ıdP ) + (ıpS − ıpP ) + (ıhS − ıhP ) ) 2 2 2 1/2 with ım = ϕ1 ı1 + ϕ2 ı2 or ϕ2 ı2 + ϕ3 ı3 (11) (6) Hansen has suggested on the basis of empirical tests the doubling of the dispersion parameter in Eq.3 Rs – 7. no protein has been introduced in the formulations since the main objective was to verify the feasibility of microsphere preparation by substituting MC in the microencapsulation process.0 17. the results obtained for PCL partial solubility parameters were ıd = 17. The concentration 0. Swelling tests 0.1. The tubes were put under magnetic stirring for 1 h.high Vm. For classical turbidimetric titration.8 9. 2007). Indeed. Indeed.3 < R < 6. the solubility sphere includes all the solvents and excludes all the non-solvents.3 7.5 < R < 7.low Vm. Then. ϕi the volume fraction.5 g/5 mL) Group contribution Swelling tests Heptane/butanol titration Hexane/butanol titration Swelling tests Swelling tests Heptane/butanol titration Hexane/butanol titration Swelling tests ıd 17.1 16. In the ideal case. an internal aqueous phase was emulsified in an organic phase. Group contribution method The most common method based on the contributions of functional groups was proposed by Van Krevelen and Hoftyzer (1976). Each non-solvent is mixed with the solvent and the molar volume Vm of these mixtures are obtained by the following equation: Vm.low + ım. N .1 3. Determination of the PCL solubility parameters 4.high = V2 V3 ϕ2 V3 + ϕ3 V2 (9) with Vi the molar volume.8. ıpP . Within this study. ıp = 4.5 g of polymer in 5 mL of solvent corresponds to the polymer concentration classically used in the literature (Barton. 4.1. the addition of a certain amount of non-solvent to a polymer solution causes the polymer precipitation. On its base.2 16.. Method PCL PCL14000 (0. ıdP = N ı S =1 dS Experiments have to be carried out in different solvents to determine the partial solubility parameters of the polymer. One of the two non-solvents is added to the polymer solution until reaching turbidity. for each chosen mixture. Bordes et al. A visual observation was conducted and the results are classified into three categories: soluble (a).5 < R < 7. (10) and the line ıapp = ısolv .0 PCL14000 (2. washed and dried. 2007). (8)) or by calculation with the minimization of the outlier number (the numbers of good solvent outside the sphere and non-solvents inside). Briefly. PCL microsphere preparation PCL microspheres were prepared by a multiple emulsion process followed by a solvent extraction/evaporation method previously described (Al Haushey et al.8 16.1 17.low + Vm.5 5.3 3.1 8.7 8.low = V1 V2 ϕ1 V2 + ϕ2 V1 and Vm.1. Then. RS = Max(4(ıdS − ıdP ) + (ıpS − ıpP ) + (ıhS − ıhP ) ) 2 2 2 1/2 (8) 3.7 8.1 17. However.3.8 6. At this moment. ıh = 8. the measurement principle consists in varying the proportions of the two types of solvent until reaching the “solubility boundary”. 1967).2.0 7. and immersed in a bath thermostated at 25 ◦ C for 24 h.2.9 8.high . this weighting converts the elliptic shape of the solubility volume to an almost spherical one. The mass fraction of the liquids provides information on the interactions between polymer molecules.5 g/5 mL) PCL65000 (0.0 4.000 g/mol (PCL65000). ıhP = N ı S =1 hS N (7) where N is the number of solvents able to solubilize the molecule. CAS number 56235 56815 57556 60297 62533 64175 64197 67561 67630 67641 67663 67685 68122 71238 71363 71410 71432 74964 75036 75058 75092 75127 75183 75310 75365 108101 108203 108247 108327 108883 108941 109433 109660 109693 109739 109897 109999 110009 110543 110634 110827 110861 110918 111400 111557 111659 111842 111875 111900 112276 a b Solvent name Carbon tetrachloride Gycerol 1. 239 .2.5 g PCL in 5 mL solvent. 2.N-dimethylformamide 1-Propanol 1-Butanol Pentanol Benzene Bromoethane Iodoethane Acetonitrile Methylene chloride Formamide Dimethyl sulfide Isopropylamine Acetyl chloride 4-Methyl-2-pentanone Isopropyl ether Acetic anhydride Propylene carbonate Toluene Cyclohexanone Dibutyl sebacate Pentane Chlorobutane n-Butylamine Diethylamine Tetrahydrofuran Furan Hexane 1. Bordes et al.2-Diethoxyethane N-methylpyrrolidone Xylenes Tritolyl phosphate tert-Butyl methyl ether Limonene Water PCL14000a c a a c b c b a a b a a b a a a c c b a a b c a b c c a c c c c a c b c c b c c b b c b b c c c c PCL14000b c a a c b c b b a b b b b a a a c c b a a b c a b c c b c c c c a c b c c b c c b b c b b c c c c PCL65000a c a a c c c c b a c a a c a a a c c c a a c c a c c c b c c c c a c c c c c c c c c c c c c c c c PCL65000b c a a c c c c b c c c c c c b b c c c a c c c b c c c b c c c c c c c c c c c c c c c c c c c c c C.5 g PCL in 5 mL solvent.4-Butanediol Cyclohexane Pyridine Morpholine Diethylenetriamine Ethylene glycol diacetate n-Octane n-Nonane 1-Octanol 2(2-Ethoxyethoxy) ethanol Triethylene glycol PCL14000a b c c c a c a c c b a c b c c c a b b b a c a b a c c c c a b c c b b c a a c c c a a c c c c c c c PCL14000b b c c c b c b c c b a c b c c c a b b b a c a b a c c c c b b c c b b c a a c c c a a c c c c c c c PCL65000a c c c c a c a c c c a c c c c c a c c c a c a c a c c c c a c c c c c c a a c c c a a c c c c c c c PCL65000b c c c c b c b c c c a c c c c c b c c c a c b c a c c c c c c c c c c c b b c c c b c c c c c c c c CAS number 75854 75898 76051 78922 78933 84662 93890 95476 95501 96220 98862 98953 100414 100516 100527 100663 102716 105588 106423 107062 107073 107108 107211 107313 107879 112403 112607 119368 121448 123422 123513 123864 123911 124185 127195 131113 141435 141786 142825 544763 554121 563804 629141 872504 1330207 1330785 1634044 5989275 7732185 Solvent name 2-Methyl-2-butanol 2.2-Dichloroethane 2-Chloroethanol Propylamine Ethylene glycol Methyl formate 2-Pentanone n-Dodecane Tetraethylene glycol Methyl salicylate Triethylamine 4-Hydroxy-4-methyl-2-pentanone 3-Methyl-1-butanol n-Butyl acetate 1. partially soluble (b) and non-soluble (c).2-Trifluoroethanol Trifluoroacetic acid 2-Butanol 2-Butanone Diethyl phthalate Ethyl benzoate o-Xylene 1.2-Propanediol Diethyl ether Aniline Ethanol Acetic acid Methanol Isopropanol Acetone Chloroform Dimethyl sulfoxide N.4-Dioxane Decane N.2-Dichlorobenzene 3-Pentanone Acetophenone Nitrobenzene Ethylbenzene Benzyl alcohol Benzaldehyde Anisole Tiethanolamine Diethyl carbonate p-Xylene 1.N-dimethylacetamide Dimethyl phthalate Ethanolamine Ethyl acetate Heptane Hexadecane Methyl propionate 3-Methyl-2-butanone 1. / International Journal of Pharmaceutics 383 (2010) 236–243 0.Table 2 Swelling test results: soluble (a). At the lowest polymer concentration.2 22. / International Journal of Pharmaceutics 383 (2010) 236–243 Table 3 Results of swelling tests: numbers of PCL solvents. the sphere radius decreased significantly as the molecular weight of PCL increased (Table 1). 3(a) and (b) shows the 98 solvents (water excluded) in the solubility parameter space and the solubility sphere for the PCL14000 (0. The results are given in Table 3 with the percentage of outliers. Furthermore.3. increasing polymer concentration significantly decreased the sphere radius. Another more common way to estimate the sphere radius is to minimize the number of outliers i. 3. Fig. It determined the value of the solubility sphere radius by using relation (8): Rs = 9. The apparent solubility parameters ıapp were calculated for each solvent according to Eqs. Among the 26 solvents of PCL14000.2 30. 4. Swelling tests PCL14000a PCL65000a PCL14000b PCL65000b a b Solvents 26 24 19 6 Non-solvents 50 73 73 83 Partial solvents 23 2 7 10 % outliers 24. furan and 1. As recommended by Hansen (2007). Three-dimensional plot of Hansen solubility parameters for 98 solvents and solubility sphere for PCL14000 (a) and PCL65000 (b) at a concentration of 0. At 2. From left to right: soluble (a). a semi-crystalline polymer. As expected. 1.5 g PCL in 5 mL solvent.1.2 g PCL was dissolved in 2 mL in closed test tubes using magnetic stirrer for one hour.240 C.5 g in 5 mL). Briefly. the solvent the furthest from the PCL in the solubility parameter space is the 2-chloroethanol. Experiments have been conducted in 99 available solvents of analytical grade and have identified 26 good solvents for PCL14000 (0. (10) and (11) and graphically represented as a function of the Hansen solubility parameters.4-dioxane. tetrahydrofuran. 23 partial solvents and 50 non-solvents. The solubility parameters of PCL are then calculated using Eq. Pictures of PCL solubility states. molecular weight had a slightly influence on the solubility parameters. partially soluble (b) and non-soluble (c).e. the num- ber of solvents outside the solubility sphere and of non-solvents within is 50 (or 50% of the studied solvents).5 g PCL in 5 mL solvent. increasing the molecular weight or the quantity of PCL to dissolve implied a decrease in polymer solubility and therefore the number of solvents and partial solvents in contrast to non-solvents (see Table 3). Test results are given in Table 2. Fig. 0. Turbidimetric titration Five solvents (methylene chloride. As expected.3 24. .5 g in 5 mL solvent. to include as many solvents in the solubility sphere and exclude as many non-solvents as possible. Bordes et al.5 g in 5 mL) respectively. water was excluded from all calculations. (7) and reported for each case in Table 1.2-dichloroethane) and two non-solvent combinations (Heptane/butanol and Hexane/butanol) were used to perform turbidimetric titration experiments.5 g in 5 mL) and PCL65000 (0.8. non-solvents and partial solvents with percentage of outliers. 2007) but gave very interesting results in the case of PCL. Hansen.2 0. 2. in the case of PCL65000. Most of solvents dissolving PCL are included in the spherical region: 20–30% are outliers. an increase in molecular weight decreased the disperse fraction of solubility parameter ıd and increased ıp and ıh . Hansen approach is only suitable for amorphous polymers (Terada and Marchessault. The mass of non-solvent inducing a persistent turbidity in the tube was measured.5 g/5 mL. 2. For such a diameter. The same evolution was observed for a given molecular weight by increasing the polymer concentration. since 76% of solvents are well-predicted. Fig. 1999. Three methods have been employed to determine the partial solubility parameters of PCL: a theoretical one (group contribution) and two experimental techniques (swelling tests and turbidimetric titration). 25 ◦ C ı ıd ıp ıh 19. PCL solubility parameters were found at the intersection between the plotted regression line obtained from Eq.5 (see Table 1) should not solubilize PCL. ıd . 4. water solubility.24 7. the solvents whose distance from PCL is greater than about 7. (6)). 80. The results are reported in Table 1. Bordes et al. according to Hansen and Beerbower (1971).C. These results are in good agreement with the values calculated by Huang et al.e.53 2. The results obtained with the method of group contributions and the swelling tests were very similar. (2004) by turbidimetric titration for ıp partial solubility parameter of poly(d.29 a The values correspond to the results obtained by Huang et al. although it becomes a par- Table 4 Evolution of PCL solubility parameters as a function of temperature.2. Nineteen solvents from this list have been used to conduct swelling tests. Fig.78 14. (10). According to Hansen theory.9 2. (10) and the line ıapp = ısolv . (2006) from experimental results obtained at 70. The determination of the solubility sphere dimensions remained difficult and the results were quite different from one method to another.79 13. titration experiments showed relatively different values particularly in the case of the polar solubility parameter ıp which seemed very low.5 g/L at 20 ◦ C) following by ethyl formate with a water solubility of about 100 g/L. (2006) by using a linear method as the three-dimensional model. ıp and ıh respectively.7 6. Indeed.43 14. From a theoretical point of view.4. Moreover. / International Journal of Pharmaceutics 383 (2010) 236–243 241 Fig. the use of an optimization method for determining the diameter limited the number of outliers at 25%.4) and acetic acid was one of the most distant (d = 8.7 17.28 7. the titration method allows the determination of the solubility volume limits. the distance between PCL and the mixture allowing turbidity in the “Hansen parameter space” (Eq. Table 4 reports the values of the PCL Hansen parameters as a function of temperature and shows the same evolution.8 70 ◦ Ca 17. The range of each partial solubility parameter was similar to those determined by the other methods (see Table 1). Identification of the substitution solvent Table 5 lists the solvents belonging to the Class 3 as defined by the European Pharmacopoeia with their partial solubility parameters and their distance to PCL in the “Hansen space”. the values of ıp were very low and seem unrealistic as the results obtained by Schenderlein et al.39 15. has been taken into account for the determination of the substitution solvent since the microencapsulation process was based on a W1 /O/W2 emulsion.l-lactide-co-glycolide). Graphical determination of PCL solubility parameters by turbidimetric titration with Heptane/butanol combination. However. the partial solubility parameters decrease as temperature increases. The dotted line is the first bisector corresponding to the line ıapp = ısolv . ıh = 7.2 7. 90. 4 (a)–(d) correspond to ıt . Experiments (♦) were carried out in five different solvents and plotted with the corresponding regression line obtained from Eq. 4.7.1. In the case of swelling tests. however. according to the distances from PCL in the “Hansen space”. .5) was obtained for the sphere radius. The values obtained for the solubility parameters of the 2 PCL were very close but a relatively wide range of values (between 4. 4 shows the results obtained for PCL14000 by using the heptane/butanol non-solvent combination. 100 and 110 ◦ C with inverse gas chromatography by Tian and Munk (1994).15 2. about 10 g/L at 20 ◦ C. Experiments allowed the identification of only 2 solvents with low toxical potential: acetic acid and anisole (methoxybenzene).8.52 2. Anisole was the only solvent very slightly soluble in water (about 1. The retained solubility parameters of PCL measured at 25 ◦ C are ıd = 17. Fig. methyl acetate and ethyl formate could be also suitable for the PCL solubilization (see Table 5).83 2.5 and 7. We have considered solvents whose water solubility was limited and close to the MC one.35 100 ◦ Ca 16. Anisole was one of the closest solvent to PCL in the solubility parameter space (d = 2. ıp = 6. the results of swelling tests showed that many theoretical PCL solvents did not dissolve the polymer at the concentrations studied.44 80 ◦ Ca 16.10 14.57 7.42 7. This limited result can be partly explained by the fact that the concept of solubility parameters is only applicable for amorphous polymers while PCL exhibits a semi-crystalline structure. An additional criterion.34 110 ◦ Ca 15.7).21 7. The radius of the solubility sphere corresponds to the solubility boundary i.28 90 ◦ Ca 16. However. Therefore anisole was chosen to perform a feasibility test conducted to obtain PCL microspheres. 1 5.8 14.1 5.242 C.8 15.7 6.3 8.6 11.7 6.5 g PCL in 5 mL.4 15.4 15.8 14.7 7. the boiling temperature of anisole (154 ◦ C) is greater than that of water and its relative density is approximately 1.7 8. Methylene chloride was replaced by anisole as PCL14000 solvent and isopropanol by 1-pentanol (2%.9 14.7 8.1 14. Unlike MC (relative density = 1.6 6.7 4. Bordes et al. CAS number 100663 141786 79209 123864 109944 78933 67641 108101 1634044 123513 71410 60297 78922 108214 98828 71363 64197 67630 78831 71238 67685 142825 109660 64175 64186 a b Solvent Anisole Ethyl acetate Methyl acetate n-Butyl acetate Ethyl formate Methyl ethyl ketone Acetone Methyl isobutyl ketone Methyl tert-butyl ether 3-Methylbutane-1-ol Pentanol Diethyl ether Butanol-2 Isopropyl acetate Isopropylbenzene Butanol-1 Acetic acid Isopropyl alcohol Isobutanol Propanol-1 Dimethyl sulfoxide Heptane Pentane Ethanol Formic acid ıd 17. Fig.3 ıP 4. the extraction time was set for the feasibility test at 24 h instead of 3 h as in the case of the MC process. The corresponding results of swelling tests for PCL14000 and PCL65000 are reported (NT = non tested).9 17.2 7.8 15.5 16 15.7 6.8 7.4 8. Fig.7 7.5 0.0 6.5 g PCL in 5 mL.7 15.5 4. . filtered and dried.6 PCL14000a a b NT c NT b b c c c c c c NT NT c a c NT c c c c c NT PCL14000b a b NT c NT b b c c c c c c NT NT c b c NT c c c c c NT PCL65000a a c NT c NT c c c c c c c c NT NT c a c NT c c c c c NT PCL65000b b c NT c NT c c c c c c c c NT NT c b c NT c c c c c NT Distance to PCL 2.1 11. the microparticles were spherical.5 15. After 24 h of extraction/evaporation. tial solvent for the PCL65000 at 2.1 11.8 16. These properties induced difficulties for the solvent extraction/evaporation step.9 5.0 5.4 7.7 8.3 7.9 5.2 3. Moreover the nature of the alcohol used to extract anisole was changed: 1-pentanol was chosen to replace isopropanol since pentanol-1 is the heaviest of the alcohol substances belonging to Fig.5 15. 4.7 8.4 5.2. Microsphere feasibility test PCL microsphere production was conducted by using the method of multiple emulsification with solvent extraction/evaporation described in Section 3.8 15. / International Journal of Pharmaceutics 383 (2010) 236–243 Table 5 Partial solubility parameters of solvents belonging to the Class 3 as defined by the European Pharmacopeia and their distance to PCL in the “Hansen space”.4 10. Therefore.2 0 0 19.1 0 15.4 9.4 16.3.3 14.2 5.9 ıh 6.8 11.2 4.9 16.8 15.6 10. PCL particles were washed.1 4.5 12. Fig.4 0 0 8.3 14.5 16. 6.8 5. 5 b).0 4. 2. SEM images of PCL microparticles obtained with anisole (a) or MC (b) as polymer solvent.3 6.3 13. v/v) in the extracting aqueous phase to remove anisole. 6 shows the particle size distribution of both the formulations reflecting quite similar granulometry.1 6. with smooth and homogeneous surface and an average diameter of 15 m (Fig.8 15.2 10.1 5 13.5 15. 5 (a) shows SEM images of the PCL microparticles obtained which were relatively spherical with rough and heterogeneous surface and an average diameter about 20 m.7 9.8 12.4 9 5.5 4.5 g/5 mL as shown by swelling tests.2 16 14.3 5.1 16 18.4 and boiling temperature = 40 ◦ C).4 4.3 7.3 8.5 2. In the case of MC.7 1.8 13.0 5. 5.8 15.5 15. Particle size distribution of microspheres obtained with anisole or MC as PCL solvent. New York.. Hansen Solubility Parameters: A User’s Handbook. 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