Rheological and mechanical properties of hydrophilic dispersions using a new hydrophobically modified polymer and Igepal (R) CO520

Elsevier Editorial System(tm) for Carbohydrate Polymers Manuscript Draft Manuscript Number: Title: Rheological and mechanical properties of hydrophilic dispersions using a new hydrophobically modified polymer and Igepal® CO520 Article Type: Research Paper Keywords: Hydrophobically modified polymer; Hydroxypropyl cellulose-methyl methacrylate; Igepal® CO520; Rheological properties; Mechanical properties; Topical application systems Corresponding Author: Full Professor Maria Rosa Jiménez-Castellanos, Full Professor Corresponding Author's Institution: University of Seville First Author: Maria Jesus Lucero, Full Professor Order of Authors: Maria Jesus Lucero, Full Professor; Carmen Claro, PhD; Marta Casas, PhD; Maria Rosa Jiménez-Castellanos, Full Professor Abstract: Hydroxypropyl cellulose-methyl methacrylate and Igepal® CO520 (different % w/w) have been characterized in aqueous-based dispersions for topical application systems. The systems have similar viscosity curves independent of the surfactant´s concentration, showing shear-thinning fluids. Also, the elastic and viscous moduli are constant and independent of critical stress values applied; however, the storage modulus was always higher than the loss modulus. Both parameters showed a slightly dependence on the applied frequency, indicating a gel-like behavior. The complex dynamic viscosity increases until 23% w/w of surfactant, keeps then constant. The hardness, compressibility and adhesiveness parameters increase when increase the Igepal® CO520 concentration. The adhesiveness properties are higher than the compressibility ones, with low values for hardness. While fracture and Hencky´s strain values increase when increase the surfactant concentration, fracture work decreased, and no relation is found to deformability modulus. Also, the dispersed system with 20% w/w of Igepal® CO520 has less stiffness than with 25 % w/w. Suggested Reviewers: Carmen Álvarez-Lorenzo Full Professor Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela carmen.alvarez.loren[email protected]s She works with aqueous-based dispersions for pharmaceutical applications Pietro Matricardi Full Professor Chemical and Pharmaceutical Technology, University of Rome [email protected] He works on polysaccharide-based gels for drug release application Thorsteinn Loftsson Full Professor Department of pharmacy , University of Iceland [email protected] Professor Loftsson works with hydrogels and topical drug delivery C/ Profesor García González, nº 2 41012 Sevilla (España) Teléfono: 954556836 Fax: 954556726 E-mail: [email protected] UNIVERSIDAD DE SEVILLA FACULTAD DE FARMACIA DEPARTAMENTO DE FARMACIA Y TECNOLOGÍA FARMACEUTICA To the Editor in Chief Carbohydrate Polymers Seville, 15 April of 2011 Dear Professor, I send you a research paper where we use a new carbohydrate polymer with potential industrial application in pharmaceutical area, with the title: "Rheological and mechanical properties of hydrophilic dispersions using a new hydrophobically modified polymer and Igepal® CO520” undertaken by my research group. Profa. Dra. Maria Rosa Jiménez-Castellanos Ballesteros Cover Letter 1 Rheological and mechanical properties of hydrophilic dispersions using a new 1 hydrophobically modified polymer and Igepal® CO520. 2 Lucero, M.J., Claro, C., Casas, M. and Jiménez-Castellanos, Mª R* 3 Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de 4 Sevilla, c/ Profesor García González, 41012, Sevilla, Spain 5 *e-mail: mro[email protected]; Departamento de Farmacia y Tecnología Farmacéutica, Facultad de 6 Farmacia, Universidad de Sevilla, c/ Profesor García González, 41012, Sevilla, Spain 7 Tel.+34 954556836; fax:+34 954556085 8 Abstract 9 Hydroxypropyl cellulose-methyl methacrylate and Igepal® CO520 (different % w/w) 10 have been characterized in aqueous-based dispersions for topical application systems. 11 The systems have similar viscosity curves independent of the surfactant´s concentration, 12 showing shear-thinning fluids. Also, the elastic and viscous moduli are constant and 13 independent of critical stress values applied; however, the storage modulus was always 14 higher than the loss modulus. Both parameters showed a slightly dependence on the 15 applied frequency, indicating a gel-like behavior. The complex dynamic viscosity 16 increases until 23% w/w of surfactant, keeps then constant. The hardness, 17 compressibility and adhesiveness parameters increase when increase the Igepal® CO520 18 concentration. The adhesiveness properties are higher than the compressibility ones, 19 with low values for hardness. While fracture and Hencky´s strain values increase when 20 increase the surfactant concentration, fracture work decreased, and no relation is found 21 to deformability modulus. Also, the dispersed system with 20% w/w of Igepal® CO520 22 has less stiffness than with 25 % w/w. 23 Manuscript Click here to view linked References 2 Key words: Hydrophobically modified polymer; Hydroxypropyl cellulose-methyl 1 methacrylate; Igepal® CO520; Rheological properties; Mechanical properties; Topical 2 application systems. 3 4 Introduction 5 In the development of pharmaceutical semisolid preparations for topical 6 application, several desirable product characteristics may be defined in order to satisfy 7 patient needs and reach the maximum clinical efficacy (Jones, Woolfson & Djokic, 8 1996; Bruschi et al., 2007). These include among others mechanical properties and 9 acceptable viscosity (Davis, 1971), because provides essential information related to 10 these preparations. 11 So, rheological properties affected to all steps of manufacture and manipulate 12 processes, and its topical application (Talukdar, Vinckier, Moldenaers & Kinget, 1996). 13 Moreover, these measures are important tools in quality control of components and final 14 product. The rheological behavior of the formulations (preparations) used in 15 pharmaceutical and cosmetics industries are characterized by flow and dynamic 16 oscillatory shear (Niraula, King & Misran, 2003). The last one, so-called ‗fingerprint‘ 17 provides information of intermolecular and interparticle forces under non-destructive 18 conditions (Lippacher, Müller & Mäder, 2001). 19 Texture profile analysis (TPA) is a technique that has been extensively 20 employed to mechanically and geometrically characterize food (Jones, Woolfson & 21 Djokic, 1996). Later, it has emerged also as a useful technique in the field of 22 pharmaceutical gel analysis (Coviello et al., 2003). From the resulting force–distance 23 and force–time plots, the hardness (the force required to attain a given deformation), 24 compressibility (the work required to deform the product during the first pass of the 25 probe), and adhesiveness (the work necessary to overcome the attractive forces between 26 the surface of the sample and the surface of the probe) are derived (Bruschi et al., 2007). 27 Also, from force–distance plots its can been obtained others mechanical parameters 28 related to stiffness or fracture of the disperse system, that allow know its structure 29 (Kaletunc, Normand, Nussinovitch & Peleg, 1991; Kampf & Nussinovitch 1997; Moya-30 Ortega, Álvarez-Lorenzo, Sigurdsson, Concheiro & Loftsson, 2010). These mechanical 31 3 properties are related with in vivo sensorial parameters, being applied to design of 1 topical pharmaceutical preparations (Jones, Woolfson, Djokic & Coulter, 1996). 2 A hydrophobically modified polymer (HMP) is a water soluble polymer, onto 3 which short hydrophobic side-chains have been grafted (Piculell, Guillemet, Thuresson, 4 Shubin & Ericsson., 1996). In a previous paper we determined the possible interaction 5 between a new hydrophobically modified polymer (HMP), hydroxypropyl cellulose-6 methyl methacrylate (HCMMA) with different surfactants. Also, we explored the 7 possibility to obtain stable dispersed system which could be used as topical dosage form 8 in pharmaceutical applications. This work demonstrated that the copolymer studied, 9 which exhibits predominant hydrophobic properties can be used to formulate long-term 10 aqueous-based dispersions by choosing the right surfactant as well as suitable batch 11 processing conditions. So, the best results were found with HCMMA/Igepal® CO520 12 system which presented a region of long term foam-like stable dispersions (Claro, 13 Muñoz, de la Fuente, Jiménez-Castellanos & Lucero, 2008). 14 Therefore, this study describes the rheological and mechanical characterization 15 of ternary systems prepared from the hydrophobically modified polymer HCMMA, the 16 surfactant Igepal® CO520 at different concentrations, and water with the aim of its 17 study as platforms for topical application systems. 18 2. Materials and methods 19 2.1. Materials 20 The ternary system was constituted by the HMP, hydroxypropyl cellulose-21 methyl methacrylate (HCMMA), synthesized as detailed in a previous work (Castellano 22 Gurruchaga & Goñi, 1997), a commercial non-ionic surfactant, the polyoxyethylene 23 (EO = 5) nonylphenyl ether (Igepal CO520®, HLB 10, Mw 441, batch 17812LO, 24 Sigma–Aldrich, Barcelona, Spain) and bidistilled water. The surfactant was used as 25 received, without any further purification. 26 2.2. Methods 27 2.2.1. Preparation of dispersions 28 Concentrated aqueous dispersion of the HCMMA/Igepal CO520® was prepared 29 with an Ultra-Turrax T18 homogenizer equipped with an S-18 N-19G turbine (IKA, 30 4 Staufen, Germany). Homogenization was carried out at 6000 rpm and the beaker 1 containing the sample was kept in a circulator bath at 30ºC for the batch operation time 2 (2 h). The detailed procedure consisted of adding the required amount of HCMMA on 3 the previously prepared aqueous solution of surfactant. The dispersion compositions 4 were: HCMMA (1.5% w/w) and Igepal CO520® (20 to 25% w/w). 5 2.2.2. Rheological characterization 6 The systems were allowed to rest at room temperature for 24 h after their 7 preparation before conducting any rheological test in order to ensure the same recent 8 shear history for all the samples and to avoid mechanical memory effects. Multi-step 9 flow curve measurements were run using a controlled-stress rheometer, RS-100 (Haake, 10 Karlsruhe, Germany), using plate & plate sensor systems of 60 mm diameter with 11 serrated surfaces. The experimental protocol consisted of applying every shear stress 12 either until an approximation to the steady-state of 0.001 was reached or until a 13 maximum time of 300 s per point. 14 Small amplitude oscillatory shear experiments were carried out in the RS-100 15 rheometer to determine the linear dynamic viscoelastic properties of samples. First of 16 all, the linear viscoelastic region for the different systems was determined by stress 17 sweeps at 1Hz. A stress amplitude of 2 Pa was used to determine the mechanical spectra 18 in a frequency range from 0.01 rad/s to 100 rad/s. 19 The analysis of results is based on the storage (G´) and loss (G´´) moduli, which 20 are related to the elastic and viscous component, respectively. Also, the complex 21 dynamic viscosity (*) are used as viscoelastic function (1): 22 * = G*/ G*= G´ + I G´´ (1) 23 where  is angular rate (rad/s (Taylor , Tanna, Sahota & Voermans, 2006). 24 All measurements were made at 25±1 ºC. Vaseline oil was used as sealing agent 25 to prevent samples from drying-out. Each measurement was made in triplicate. The 26 sensor systems used in this work were calibrated with SUA1 standard fluid (Hudson & 27 Jones, 1993). 28 2.2.3. Mechanical characterization 29 5 Mechanical properties of the hydrophilic dispersions studies were determined by 1 uniaxial compression with a load cell of 5 Kg force. Texture analyzer (TA-XTA2, 2 Stable Micro Systems, UK) was used controlled by a software. A standard extrusion 3 disc with a 35 mm diameter (A/BE) was used as the sensor. Hardness, compressibility 4 and adhesiveness were measured. 5 The force versus time data was converted to a true stress () and Hencky´s strain 6 (H), relationship using the following substitutions (2) and (3) (Kampf & Nussnovitch, 7 1997; Ribeiro, Rodrigues, Sabadini & Cunha, 2004). 8 (2) 9 (3) 10 where F is the momentary force at time t, H is the height at time t, A0 is the cross-11 sectional area of the original gel (962.115 mm2) and H0 is the initial length when the 12 compression starts (4 mm). 13 Stress (f) and strain (f) fractures were determined as the maximum point of the 14 true stress-Hencky strain curve and the fracture work (Wf) was the area under curve of 15 the fracture sone (Wium & Qvist 1997). Since gels are viscoelastic rather than elastic 16 and are usually subjected to large compression during testing, the strict definition of 17 Young´s modulus as an expression of a food´s stress-strain ratio was replaced by the 18 ´modulus of deformability´ (MD), (Kampf & Nussnovitch, 1997; Moya-Ortega, Álvarez-19 Lorenzo, Sigurdsson, Concheiro & Loftsson, 2010) defined as the slope of the linear 20 portion of the stress-strain relationship. MD was determined taking into consideration 21 between 47 and 80 data. This deformability module is a stiffness index and is widely 22 used to characterized gels and soft materials (Konstance, 1993). 23 Force relaxation curves were normalized and linearized by the following 24 equation (4) (Kampf & Nussnovitch, 1997). 25 (4) 26 where F0 and F(t) are the initial and momentary forces and k1 (min) and k2 are constants. 27 The constant k2 derived from equation (5), was used to calculate an asymptotic residual 28 modulus, EA, that serves as a measure of gel solidity (Peleg & Pollak, 1982). 29 6 (5) 1 where  is the imposed strain and A(  ) is the corresponding calculated cross-sectional 2 area of the deforming sample. 3 Measures were made after 24 hours kept at 25±1 ºC. 60 g of sample were put in 4 a standard recipient of 50 mm diameter. Before assay, the distance initial measure (70 5 mm from the recipient base) and the penetration deep (4 mm since the sensor contact 6 the sample) were determined. Speed before, during and after assay was 2 mm/s. Each 7 measurement was made in triplicate. 8 3. Results and Discussions 9 3.1. Rheological characterization 10 Viscosity curves of dispersions at 25 ºC are shown in Figure 1. All systems have 11 similar viscosity curves independent of the surfactant´s concentration. Also, all of them 12 show shear-thinning fluids which means that their viscosity decreases as the shear rate 13 increases. The shear-thinning behavior may be regarded as arising from modifications in 14 macromolecular organization in the solution as the shear rate changes. At low shear 15 rates, the disruption of entanglements by the imposed shear is balanced by the formation 16 of new ones, so that no net change in entanglements occurs; it is the Newtonian plateau 17 region, where the viscosity has a constant value. For higher shear rates, disruption 18 predominates over formation of new entanglements, molecules align in the direction of 19 flow and the apparent viscosity decreases with increasing shear rate. As a consequence, 20 the shear rate corresponding to the transition from Newtonian to shear-thinning 21 behavior moves to lower values as the concentration increases (Badiger, Lutz & Wolf, 22 2000; Rudraraju & Wyandt, 2005; Sittikijyothin, Torres & Gonçalves, 2005). 23 The shear thinning behavior can be fitted to well within experimental error by 24 the Ostwald–de Waele or ―Power Law‖ model (Medina-Torres, Brito-De La Fuente, 25 Torrestiana-Sanchez, & Katthain, 2000) given by (6): 26 (6) 27 where k is the consistency index (Pa.s), is the shear rate (s-1) and n the fluid behavior 28 index. The parameters n and k are obtained by linear regression analysis. To Newtonian 29 fluids n=1, to pseudoplastic fluids n<1 and to dilatants fluids n>1. 30 13 - Niraula, B., King, T.C. & Misran, M. (2003). Rheology properties of dodecyl-β-D-1 maltoside stabilised mineral oil-in-water emulsions. Colloids and Surfaces A: 2 Physicochemical Engineering Aspects, 231, 159-172. 3 - Peleg, M. & Pollak, N. (1982). The problem of equilibrium conditions in stress 4 relaxation analyses of solid foods. Journal of Texture Studies, 13, 1-11. 5 - Piculell, L., Guillemet, F., Thuresson, D., Shubin,V. & Ericsson, O. (1996). Binding of 6 surfactants to hydrophobically modified polymers. Advances in Colloid Interface 7 Science, 63, 1–21. 8 - Ribeiro, K.O., Rodrigues, M.I., Sabadini, E. & Cunha, R.I. (2004). Mechanical 9 properties of acid sodium caseinate--carrageenan gels: effect of co-solute addition. 10 Food Hydrocolloids, 18, 71-79. 11 - Rudraraju, V.S. & Wyandt, Ch. M. (2005). Rheological characterization of 12 microcrystalline cellulose/sodium carboxymethyl cellulose hydrogels using a controlled 13 stress rheometer: part I. International Journal of Pharmaceutics, 292, 53-61. 14 - Sittikijyothin, W., Torres, D. & Gonçalves, M.P. (2005). Modelling the rheological 15 behaviour of galactomannan aqueous solutions. Carbohydrate Polymers, 59, 339-350. 16 - Talukdar, M.M., Vinckier, I., Moldenaers, P. & Kinget, R. (1996). Rheological 17 characterisation of xanthan gum and hydroxypropylmethylcellulose with respect to 18 controlled-release drug delivery. Journal of Pharmaceutical Sciences, 85, 537-540. 19 - Taylor, M.J., Tanna, S., Sahota, T.S., Voermans, B. (2006). Rheological 20 characterisation of dextran-concavalin. A mixtures as a basis for a self-regulated drug 21 delivery device. European Journal of Pharmaceutics and Biopharmaceutics, 62, 94-22 100. 23 - Torres, L.G., Iturbe, R., Snowden, M.J., Chowdhry, B.Z. & Leharne, S.A. (2007). 24 Preparation of o/w emulsions stabilized by solid particles and their characterization by 25 oscillatory rheology. Colloids and Surfaces A: Physicochemical Engineering Aspects, 26 302, 439-448. 27 - Wium, H. & Qvist K.B. (1997). Rheological properties of UF-feta cheese determined 28 by uniaxial compression and dynamic testing. Journal of Texture Studies, 28, 435-454. 29 Table I. Characteristic parameters of Ostwald-de Waele or Power Law and Cross model for the systems HCMMA-Igepal® CO520-water studied at 25ºC. Igepal® CO520 (%w/w) Power Law Model Cross Model k (Pa.s) n r2 (Pa.s) (s) m r2 20 7.30 0.06 0.970 27175 1250 0.94 0.980 21 14.57 0.08 0.980 32724 1250 0.96 0.951 22 16.72 0.07 0.990 34295 1429 0.95 0.977 23 22.05 0.12 0.950 53302 2000 0.95 0.898 24 33.61 0.18 0.920 53408 2041 0.98 0.991 25 47.16 0.20 0.930 61370 2000 0.95 0.964 Table I Table II. Parameters obtained in mechanical characterization of different systems HCMMA-Igepal® CO520-water at 25ºC. Parameters Surfactant (% w/w) 20 21 22 23 24 25 Hardness (N) 0.321 ± 0.005 0.350 ± 0.008 0.392 ± 0.013 0.418 ± 0.005 0.504 ± 0.020 0.546 ± 0.008 Compressibility (N·mm) 0.848 ± 0.048 0.897 ± 0.090 1.066 ± 0.049 1.019 ± 0.047 1.242 ± 0.118 1.263 ± 0.085 Adhessiveness (N·mm) 1.038 ± 0.056 1.229 ± 0.068 1.256 ± 0.025 1.445 ± 0.039 1.678 ± 0.127 1.862 ± 0.076 Fracture strain (Pa) 2065 2247 2566 2497 3084 3000 Hencky´s strain 0.3524 0.2678 0.2887 0.4700 0.5255 0.6867 Deformability modulus (Pa) 6850 6784 9767 2176 3174 1672 Fracture work (J/m2) 232.02 154.59 185.26 98.92 101.48 80.32 k1 (s) 0.001 0.001 0.001 0.002 0.002 0.003 k2 1.006 1.007 1.008 1.008 1.010 1.012 Ea (Pa) 338.96 364.07 404.20 404.20 504.25 603.91 Table II Table III. Parameters obtained in mechanical characterization of different systems Igepal® CO520-water at 25ºC. Parameters Surfactant (% w/w) 20 21 22 23 24 25 Hardness (N) 0.128 ± 0.001 0.136 ± 0.002 0.168 ± 0.006 0.162 ± 0.003 0.205 ± 0.002 0.275 ± 0.003 Compressibility (N·mm) 0.385 ± 0.004 0.398 ± 0.007 0.473 ± 0.004 0.459 ± 0.011 0.543 ± 0.015 0.698 ± 0.028 Adhessiveness (N·mm) 0.313 ± 0.001 0.331 ± 0.007 0.423 ± 0.002 0.358 ± 0.020 0.444 ± 0.008 0.746 ± 0.006 Table III Figure 1. Viscosity curves of different systems HCMMA-Igepal® CO520 (% w/w)- water at 25ºC. Figure 1 Figure 2. Storage (G’) and loss (G’’) moduli values of different systems HCMMA- Igepal® CO520 (%w/w)-water at 25 ºC. Figure 2 Figure 3. Storage (G´) and loss (G´´) moduli vs. frequency sweep of different systems HCMMA-Igepal® CO520 (%w/w)-water at 25 ºC. Figure 3 Figure 4. Dinamic viscosity (η*) vs. surfactant´s concentration of the different systems of HCMMA-Igepal® CO520-water at 25 ºC. Figure 4 Figure 5. Typical mechanical curves obtained with the texture analyzer (force v.s. time and force v.s. displacement) to the different systems of HCMMA-Igepal® CO520 (%w/w)-water at 25 ºC. Figure 5 We work with hydrophilic dispersions using hydroxypropylcellulose-methyl methacrylate.> We prepare systems with this hydrophobically modified polymer and a surfactant. > We study rheological properties with different surfactant´s concentration. > Systems have similar viscosity curves and a shear-thinning behavior. > These gels are adequate to be base excipients for topical drug administration. *Highlights