Comparison between polymeric excipients using SeDeM expert system in combination with mathematical modeling and quality control tools
Abstract
Based on the quality by design approach, we used the SeDeM expert system to assess seven polymers of different chemical nature and molecular weight for their use in direct compression. Because the SeDeM system fails by not evaluating the mechanical properties of materials, we used the Heckel and the Ryshkewitch-Duckworth mathematical models to study compressibility and compactibility of the materials, respectively. The deformation mechanism and the bonding capacity of the polymers were identified, evidencing that polyethylene oxide 301 and 303 and the carbomer homopolymer had an outstanding performance. In addition, tools such as control charts of the statistical process control and indices of the potential and actual capability in a polymer compaction process were implemented, using the weight and tablet breaking force as critical attributes of quality. In these studies, polyethylene oxide 301 and 303, hydroxypropylmethyl cellulose, and hydroxypropyl cellulose HF had the best performance and less breaking force variation. On the other hand, carbomer homopolymer exhibited the best outcomes in terms of weight variation. The use of the mentioned tools contributed to achieve a better knowledge of the properties and behavior of materials to make a rational selection of the components of a formulation.
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SUPPLEMENTARY MATERIAL Comparison between polymeric excipients using SeDeM expert system in combination with mathematical modeling and quality control tools Oswaldo Castañeda Hernández1,2, Juan Domínguez-Robles2, Isidoro Caraballo Rodríguez2, María Josefa Bernad Bernad3, Luz María Melgoza Contreras4* 1Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, 04960, Ciudad de México, México. 2Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Seville, Spain. 3Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, México. 4Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, 04960, Ciudad de México, México. *Corresponding author: Luz María Melgoza Contreras Email: [email protected]
Table S1. Experimental values for the polymeric excipients with SeDeM expert system tests Parameter HPMC 60 HPMC 75 PEO 301 PEO 303 CBP 71G HPC MF HPC HF Db (g/mL) 0.3879 ± 0.0112 0.4153 ± 0.0040 0.3985 ± 0.0023 0.4085 ± 0.0073 0.3778 ± 0.0039 0.3884 ± 0.0045 0.3483 ± 0.0083 Dt (g/mL) 0.5147 ± 0.0075 0.5698 ± 0.0064 0.4687 ± 0.0059 0.4856 ± 0.0045 0.4490 ± 0.0082 0.4743 ± 0.0095 0.4639 ± 0.0138 CI (%) 24.64 ± 1.51 27.10 ± 1.37 14.97 ± 0.74 15.87 ± 2.09 15.84 ± 2.04 18.10 ± 0.82 24.92 ± 0.78 HR 1.33 ± 0.03 1.37 ± 0.03 1.17 ± 0.01 1.18 ± 0.03 1.19 ± 0.03 1.22 ± 0.01 1.33 ± 0.01 Ie 0.6363 ± 0.0567 0.6529 ± 0.0388 0.3755 ± 0.0178 0.3891 ± 0.0576 0.4195 ± 0.0571 0.4658 ± 0.0179 0.7155 ± 0.0213 Icd 229.87 ± 7.61 185.75 ± 7.76 940.27 ± 38.47 997.08 ± 39.72 333.85 ± 17.42 93.82 ± 8.77 172.33 ± 8.72 AR (θ) 35.17 ± 0.36 28.14 ± 0.73 20.06 ± 3.02 22.31 ± 3.19 30.96 ± 2.33 33.07 ± 0.90 33.41 ± 1.34 t’’ (s/100 g) 13.19 ± 2.26 4.74 ± 0.78 3.13 ± 0.72 3.14 ± 0.57 6.07 ± 1.65 5.54 ± 0.05 7.26 ± 0.0.15 LOD (%) 4.60 ± 0.007 5.68 ± 0.00 0.00 ± 0.00 0.76 ± 0.00 7.25 ± 0.01 0.89 ± 0.37 0.89 ± 0.41 H (%) 9.76 ± 0.022 8.90 ± 0.007 0.44 ± 0.001 0.86 ± 0.003 11.13 ± 0.008 0.53 ± 0.25 1.61 ± 0.67 Iθ 8.59x10-3 ± 0.00 1.11x10-2 ± 0.00 1.10x10-3 ± 0.00 3.77x10-3 ± 0.00 3.47x10-3 ± 0.00 6.70 x10-3 ± 0.00 8.19 x10-3 ± 0.00 < 50 µm (%) 28.32 ± 0.18 24.27 ± 0.14 3.82 ± 0.01 3.99 ± 0.01 2.99 ± 0.19 0.69 ± 0.01 2.44 ± 0.01
Modified SeDeM expert diagram system Mamidi et al. have previously proposed the inclusion of two new parameters to the conventional SeDeM expert diagram system, which are related with the mechanical performance of materials: compressibility and compactibility [1]. These two parameters are unavailable in the traditional approach of SeDeM methodology. The authors of this work claimed that compressibility and compactibility could be treated as independent parameters. Moreover, their acceptance limits for the modified SeDeM methodology are defined taking as reference previous publications in the physics of powder compression area. Compressibility was defined as function of yield pressure (Py), while compactibility was defined in terms of the maximum tensile strength value (σTmax) at zero porosity [1]. Figure S1 is showing the modified SeDeM diagrams including these two new parameters and all the polymeric excipients had a similar behavior above the critical radial value for both compressibility and compactibility. These results can be attributable to the plastic deformation properties of the polymers. Table S2 presents the data with de modified SeDeM methodology. Since Py and σTMax are considered as mechanical properties and are related with volume reduction and tablet breaking force behavior, we decided to include them into Compressibility incidence. It has to be pointed out that such incidence improved with the addition of the new compressibility and compactibility parameters for all the polymers, while the other incidences kept their average values. A significant increase was produced with the inclusion of these mechanical parameters since PI changed from non-acceptable values to acceptable for HPMC 60 and HPC MF, while CBP 71G is still being considered as the only polymer that could not be suitable for direct compression. On the other hand, PPI and GCI values are above the acceptable limit and all the polymers could be considered as suitable for direct compression manufacturing processes. The approach of Mamidi et al. proposal may be appropriate for the introduction of mechanical parameters into SeDeM system [1]. However, deeper research should be performed to include these parameters in the SeDeM expert system since mathematical models represent an additional source of knowledge and their application is not only limited to a simple value. For instance, compressibility analysis through Heckel model allows the determination of yield pressure (Py) that represents the needed pressure for particles deformation, but the model also represents a tool for a deep understanding of material’s properties. In our evaluation, we detected slope changes (coupled to an increase in standard deviation in the measurements) that are attributable to a viscoelastic
behavior and work hardening for some polymers (HPMC 60, HPMC 75 and PEO 301) beyond 250 MPa of compaction pressure. Regarding the compactibility parameter, Mamidi et al. used the Leuenberger model, which considers a non-linear relationship between compacts’ tensile strength and relative density with a percolation approach, and thus it is slightly different to Ryshkewitch-Duckworth model [2,3]. The latter considers a relation between tensile strength as function of porosity or solid fraction. Indeed, Ryshkewitch-Duckworth model was initially used for studying ceramic materials, but it has been successfully applied to study the mechanical properties of pharmaceutical materials. Ryshkewitch-Ducwkorth model allows to calculate the maximum theoretical tensile strength at zero porosity (σTmax or σT0), but it also gives information about the bonding capacity of materials (k) through the slope of the model regression (the higher the k value, the greater the capacity of the materials to establish interparticle bonds).
a) b) c) d) e) f) g) Figure S1. Modified SeDeM diagrams of the polymeric excipients: HPMC 60 (a), HPMC 75 (b), PEO 301 (c), PEO 303 (d), CBP 71G (e), HPC MF (f), and HPC HF (g).
Table S2. Radial values indexing Py and σTMax values PARAMETERS (RADIAL VALUES) INCIDENCES INDICES Material Db * Dt * Ie * CI * Icd * Py Ts HR* AR* t’’ % RH %H %< 50 µm Iθ Dimension Compressibility Flowability/ Powder flow Lubricity/ Stability Lubricity/ Dosage PI PPI GCI HPMC 60 3.88 5.15 5.30 4.93 10.0 6.43 8.96 8.36 2.97 3.41 9.94 4.44 4.34 4.29 4.51 7.12 4.91 7.19 4.32 0.50 5.89 5.60 HPMC 75 4.15 5.70 5.44 5.42 9.28 6.35 8.62 8.14 4.37 7.63 9.94 5.55 5.15 5.57 7.02 6.71 6.71 7.74 5.36 0.86 6.52 6.21 CBP 71G 3.78 4.49 3.50 3.17 10.0 5.71 10.0 9.06 3.81 6.97 2.75 4.44 9.40 1.74 4.13 6.47 6.61 3.59 5.57 0.43 5.62 5.36 PEO 301 3.99 4.69 3.13 2.99 10.0 5.88 10.0 9.12 5.99 8.43 10 9.62 9.24 1.10 4.34 6.40 7.85 9.81 5.17 0.64 6.73 6.40 PEO 303 4.09 4.86 3.24 3.17 10.0 5.64 10.0 9.05 5.54 8.43 9.56 9.57 9.20 1.89 4.47 6.41 7.67 9.57 5.54 0.64 6.73 6.41 HPC MF 3.88 4.74 3.88 3.62 4.69 5.97 10.0 8.89 3.39 7.23 9.11 9.20 9.86 3.35 4.31 5.63 6.50 9.42 6.61 0.50 6.31 6.01 HPC HF 3.48 4.64 5.96 4.98 8.62 6.01 10.0 8.34 3.32 6.37 9.10 9.19 9.51 4.10 4.06 7.11 6.01 9.15 6.81 0.64 6.69 6.37
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