Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis
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摘要
The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr's index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables(impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.
The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr's index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables(impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.
The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr's index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables(impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.
引文
[1] Badawy SIF, Menning MM, Gorko MA, Gilbert DL. Effect of process parameters on compressibility of granulation manufactured in a high-shear mixer. Int J Pharm2000;198(1):51–61.
[2] Ho R, Dilworth SE, Williams DR, Heng JY. Role of surface chemistry and energetics in high shear wet granulation. Ind Eng Chem Res 2011;50(16):9642–9.
[3] Rahmanian N, Ghadiri M, Jia X, Stepanek F. Characterisation of granule structure and strength made in a high shear granulator. Powder Technol 2009;192(2):184–94.
[4] Hansuld E, Briens L. A review of monitoring methods for pharmaceutical wet granulation. Int J Pharm2014;472(1):192–201.
[5] Cavinato M, Franceschinis E, Cavallari S, Realdon N,Santomaso A. Relationship between particle shape and some process variables in high shear wet granulation using binders of different viscosity. Chem Eng J 2010;164(2):292–8.
[6] Heged u?sá, Pintye-Hódi K. Influence of the type of the high-shear granulator on the physico-chemical properties of granules. Chem Eng Process 2007;46(10):1012–19.
[7] Pathare PB, Ba s?N, Fitzpatrick JJ, Cronin K, Byrne EP. Effect of high shear granulation process parameters on the production of granola cereal aggregates. Biosyst Eng2011;110(4):473–81.
[8] Chitu TM, Oulahna D, Hemati M. Rheology, granule growth and granule strength:application to the wet granulation of lactose–MCC mixtures. Powder Technol 2011;208(2):441–53.
[9] Ennis BJ. Theory of granulation:an engineering perspective.Handbook of pharmaceutical granulation technology, 3.Taylor&Francis Group; 2010. p. 6–58.
[10] Iveson SM, Litster JD, Hapgood K, Ennis BJ. Nucleation,growth and breakage phenomena in agitated wet granulation processes:a review. Powder Technol2001;117(1–2):3–39.
[11] Realpe A, Velázquez C. Growth kinetics and mechanism of wet granulation in a laboratory-scale high shear mixer:effect of initial polydispersity of particle size. Chem Eng Sci2008;63(6):1602–11.
[12] Sakr WF, Ibrahim MA, Alanazi FK, Sakr AA. Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry. Saudi Pharm J 2012;20(1):9–19.
[13] Kristensen J, Sch?fer T, Kleinebudde P. Direct pelletization in a rotary processor controlled by torque measurements. II:effects of changes in the content of microcrystalline cellulose. AAPS PharmSci 2000;2(3):45–52.
[14] Benali M, Gerbaud V, Hemati M. Effect of operating conditions and physico-chemical properties on the wet granulation kinetics in high shear mixer. Powder Technol2009;190(1):160–9.
[15] Butensky M, Hyman D. Rotary drum granulation. An experimental study of the factors affecting granule size. Ind Eng Chem Res 1971;10(2):212–19.
[16] Liu H, Wang K, Schlindwein W, Li M. Using the Box—Behnken experimental design to optimise operating parameters in pulsed spray fluidised bed granulation. Int J Pharm 2013;448(2):329–38.
[17] Mangwandi C, Albadarin AB, Ala’a H, Allen SJ, Walker GM.Optimisation of high shear granulation of multicomponent fertiliser using response surface methodology. Powder Technol 2013;238:142–50.
[18] Charoo NA, Ali AA. Quality risk management in pharmaceutical development. Drug Dev Ind Pharm2013;39(7):947–60.
[19] Lawrence XY. Pharmaceutical quality by design:product and process development, understanding, and control. Pharm Res 2008;25(4):781–91.
[20] Lee YL, Kim MS, Park MY, Han K. Quality by design:understanding the formulation variables and optimization of metformin hydrochloride 750 mg sustained release tablet by Box–Behnken design. J Pharm Investig 2012;42(4):213–20.
[21] Choi, D.H., Kim, YS., Kim, DD. et al. Journal of Pharmaceutical Investigation(2018). https://doi.org/10.1007/s40005-018-0386-4.
[22] Habib Y, Augsburger L, Reier G, Wheatley T, Shangraw R.Dilution potential:a new perspective. Pharm Dev Technol1996;1(2):205–12.
[23] Santana H, González Y, Campana PT, et al. Screening for stability and compatibility conditions of recombinant human epidermal growth factor for parenteral formulation:effect of pH, buffers, and excipients. Int J Pharm2013;452(1):52–62.
[24] Heckel R. Density-pressure relationships in powder compaction. Trans Metall Soc AIME 1961;221(4):671–5.
[25] Kawakita K, Tsutsumi Y. An empirical equation of state for powder compression. Jpn J Appl Phys 1965;4(1):56.
[26] Gupta S, Jhawat V. Quality by design(Qb D)approach of pharmacogenomics in drug designing and formulation development for optimization of drug delivery systems. J Control Release 2017;245:15–26.
[27] Vora C, Patadia R, Mittal K, Mashru R. Risk based approach for design and optimization of site specific delivery of isoniazid. J Pharm Investig 2015;45(2):249–64.
[28] Zhang L, Mao S. Application of quality by design in the current drug development. Asian J Pharm Sci2017;12(1):1–8.
[29] Koide T, Nagato T, Kanou Y, et al. Detection of component segregation in granules manufactured by high shear granulation with over-granulation conditions using near-infrared chemical imaging. Int J Pharm2013;441(1):135–45.
[30] Willecke N, Szepes A, Wunderlich M, Remon JP, Vervaet C, De Beer T. Identifying overarching excipient properties towards an in-depth understanding of process and product performance for continuous twin-screw wet granulation. Int J Pharm 2017;522(1):234–47.
[31] Fouad SA, Basalious EB, El-Nabarawi MA, Tayel SA.Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot:in vitro/in vivo evaluation. Int J Pharm 2013;453(2):569–78.
[32] Huang YB, Tsai YH, Lee SH, Chang JS, Wu PC. Optimization of pH-independent release of nicardipine hydrochloride extended-release matrix tablets using response surface methodology. Int J Pharm 2005;289(1):87–95.
[33] Huang YB, Tsai YH, Yang WC, Chang JS, Wu PC, Takayama K.Once-daily propranolol extended-release tablet dosage form:formulation design and in vitro/in vivo investigation. Eur J Pharm Biopharm 2004;58(3):607–14.
[34] Rahmanian N, Ghadiri M, Ding Y. Effect of scale of operation on granule strength in high shear granulators. Chem Eng Sci2008;63(4):915–23.
[35] Ghorab MK, Adeyeye MC. High shear mixing granulation of ibuprofen andβ-cyclodextrin:effects of process variables on ibuprofen dissolution. AAPS PharmSciTech 2007;8(4):25–33.
[36] Badawy SI, Narang AS, LaMarche K, Subramanian G,Varia SA. Mechanistic basis for the effects of process parameters on quality attributes in high shear wet granulation. Int J Pharm 2012;439(1):324–33.
[37] Knight P, Johansen A, Kristensen H, Schaefer T, Seville J. An investigation of the effects on agglomeration of changing the speed of a mechanical mixer. Powder Technol2000;110(3):204–9.
[38] Ohno I, Hasegawa S, Yada S, Kusai A, Moribe K, Yamamoto K.Importance of evaluating the consolidation of granules manufactured by high shear mixer. Int J Pharm2007;338(1):79–86.
[39] Iskandarani B, Shiromani P, Clair J. Scale-up feasibility in high-shear mixers:determination through statistical procedures. Drug Dev Ind Pharm 2001;27(7):651–7.
[40] Ramaker J, Jelgersma MA, Vonk P, Kossen N. Scale-down of a high-shear pelletisation process:flow profile and growth kinetics. Int J Pharm 1998;166(1):89–97.
[41] Adolfsson A?, Nystr?m C. Tablet strength, porosity, elasticity and solid state structure of tablets compressed at high loads.Int J Pharm 1996;132(1):95–106.
[42] Osei-Yeboah F, Zhang M, Feng Y, Sun CC. A formulation strategy for solving the overgranulation problem in high shear wet granulation. J Pharm Sci 2014;103(8):2434–40.
[43] Sun CC. A classification system for tableting behaviors of binary powder mixtures. Asian J Pharm Sci 2016;11(4):486–91.
[44] Thapa P, Lee AR, Choi DH, Jeong SH. Effects of moisture content and compression pressure of various deforming granules on the physical properties of tablets. Powder Technol 2017;310:92–102.
[45] Basalious EB, Shawky N, Badr-Eldin SM. SNEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I:development and optimization.Int J Pharm 2010;391(1):203–11.
[46] Tung NT, Hung MV, Vo XM, Nguyen TH, Pham TMH.Formulation optimization of orally disintegrating tablets containing solid dispersion of felodipine and hydroxypropyl methylcellulose using face-centered central composite design. J Pharm Investig 2014;44(2):111-8.
[47] Roopwani R, Buckner IS. Understanding deformation mechanisms during powder compaction using principal component analysis of compression data. Int J Pharm2011;418(2):227–34.
[48] Rajalahti T, Kvalheim OM. Multivariate data analysis in pharmaceutics:a tutorial review. Int J Pharm2011;417(1):280–90.
[49] Cui Y, Song X, Chuang K, et al. Variable selection in multivariate modeling of drug product formula and manufacturing process. J Pharm Sci 2012;101(12):4597–607.
[50] Paul S, Taylor LJ, Murphy B, et al. Powder properties and compaction parameters that influence punch sticking propensity of pharmaceuticals. Int J Pharm2017;521(1):374–83.
[2] Ho R, Dilworth SE, Williams DR, Heng JY. Role of surface chemistry and energetics in high shear wet granulation. Ind Eng Chem Res 2011;50(16):9642–9.
[3] Rahmanian N, Ghadiri M, Jia X, Stepanek F. Characterisation of granule structure and strength made in a high shear granulator. Powder Technol 2009;192(2):184–94.
[4] Hansuld E, Briens L. A review of monitoring methods for pharmaceutical wet granulation. Int J Pharm2014;472(1):192–201.
[5] Cavinato M, Franceschinis E, Cavallari S, Realdon N,Santomaso A. Relationship between particle shape and some process variables in high shear wet granulation using binders of different viscosity. Chem Eng J 2010;164(2):292–8.
[6] Heged u?sá, Pintye-Hódi K. Influence of the type of the high-shear granulator on the physico-chemical properties of granules. Chem Eng Process 2007;46(10):1012–19.
[7] Pathare PB, Ba s?N, Fitzpatrick JJ, Cronin K, Byrne EP. Effect of high shear granulation process parameters on the production of granola cereal aggregates. Biosyst Eng2011;110(4):473–81.
[8] Chitu TM, Oulahna D, Hemati M. Rheology, granule growth and granule strength:application to the wet granulation of lactose–MCC mixtures. Powder Technol 2011;208(2):441–53.
[9] Ennis BJ. Theory of granulation:an engineering perspective.Handbook of pharmaceutical granulation technology, 3.Taylor&Francis Group; 2010. p. 6–58.
[10] Iveson SM, Litster JD, Hapgood K, Ennis BJ. Nucleation,growth and breakage phenomena in agitated wet granulation processes:a review. Powder Technol2001;117(1–2):3–39.
[11] Realpe A, Velázquez C. Growth kinetics and mechanism of wet granulation in a laboratory-scale high shear mixer:effect of initial polydispersity of particle size. Chem Eng Sci2008;63(6):1602–11.
[12] Sakr WF, Ibrahim MA, Alanazi FK, Sakr AA. Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry. Saudi Pharm J 2012;20(1):9–19.
[13] Kristensen J, Sch?fer T, Kleinebudde P. Direct pelletization in a rotary processor controlled by torque measurements. II:effects of changes in the content of microcrystalline cellulose. AAPS PharmSci 2000;2(3):45–52.
[14] Benali M, Gerbaud V, Hemati M. Effect of operating conditions and physico-chemical properties on the wet granulation kinetics in high shear mixer. Powder Technol2009;190(1):160–9.
[15] Butensky M, Hyman D. Rotary drum granulation. An experimental study of the factors affecting granule size. Ind Eng Chem Res 1971;10(2):212–19.
[16] Liu H, Wang K, Schlindwein W, Li M. Using the Box—Behnken experimental design to optimise operating parameters in pulsed spray fluidised bed granulation. Int J Pharm 2013;448(2):329–38.
[17] Mangwandi C, Albadarin AB, Ala’a H, Allen SJ, Walker GM.Optimisation of high shear granulation of multicomponent fertiliser using response surface methodology. Powder Technol 2013;238:142–50.
[18] Charoo NA, Ali AA. Quality risk management in pharmaceutical development. Drug Dev Ind Pharm2013;39(7):947–60.
[19] Lawrence XY. Pharmaceutical quality by design:product and process development, understanding, and control. Pharm Res 2008;25(4):781–91.
[20] Lee YL, Kim MS, Park MY, Han K. Quality by design:understanding the formulation variables and optimization of metformin hydrochloride 750 mg sustained release tablet by Box–Behnken design. J Pharm Investig 2012;42(4):213–20.
[21] Choi, D.H., Kim, YS., Kim, DD. et al. Journal of Pharmaceutical Investigation(2018). https://doi.org/10.1007/s40005-018-0386-4.
[22] Habib Y, Augsburger L, Reier G, Wheatley T, Shangraw R.Dilution potential:a new perspective. Pharm Dev Technol1996;1(2):205–12.
[23] Santana H, González Y, Campana PT, et al. Screening for stability and compatibility conditions of recombinant human epidermal growth factor for parenteral formulation:effect of pH, buffers, and excipients. Int J Pharm2013;452(1):52–62.
[24] Heckel R. Density-pressure relationships in powder compaction. Trans Metall Soc AIME 1961;221(4):671–5.
[25] Kawakita K, Tsutsumi Y. An empirical equation of state for powder compression. Jpn J Appl Phys 1965;4(1):56.
[26] Gupta S, Jhawat V. Quality by design(Qb D)approach of pharmacogenomics in drug designing and formulation development for optimization of drug delivery systems. J Control Release 2017;245:15–26.
[27] Vora C, Patadia R, Mittal K, Mashru R. Risk based approach for design and optimization of site specific delivery of isoniazid. J Pharm Investig 2015;45(2):249–64.
[28] Zhang L, Mao S. Application of quality by design in the current drug development. Asian J Pharm Sci2017;12(1):1–8.
[29] Koide T, Nagato T, Kanou Y, et al. Detection of component segregation in granules manufactured by high shear granulation with over-granulation conditions using near-infrared chemical imaging. Int J Pharm2013;441(1):135–45.
[30] Willecke N, Szepes A, Wunderlich M, Remon JP, Vervaet C, De Beer T. Identifying overarching excipient properties towards an in-depth understanding of process and product performance for continuous twin-screw wet granulation. Int J Pharm 2017;522(1):234–47.
[31] Fouad SA, Basalious EB, El-Nabarawi MA, Tayel SA.Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot:in vitro/in vivo evaluation. Int J Pharm 2013;453(2):569–78.
[32] Huang YB, Tsai YH, Lee SH, Chang JS, Wu PC. Optimization of pH-independent release of nicardipine hydrochloride extended-release matrix tablets using response surface methodology. Int J Pharm 2005;289(1):87–95.
[33] Huang YB, Tsai YH, Yang WC, Chang JS, Wu PC, Takayama K.Once-daily propranolol extended-release tablet dosage form:formulation design and in vitro/in vivo investigation. Eur J Pharm Biopharm 2004;58(3):607–14.
[34] Rahmanian N, Ghadiri M, Ding Y. Effect of scale of operation on granule strength in high shear granulators. Chem Eng Sci2008;63(4):915–23.
[35] Ghorab MK, Adeyeye MC. High shear mixing granulation of ibuprofen andβ-cyclodextrin:effects of process variables on ibuprofen dissolution. AAPS PharmSciTech 2007;8(4):25–33.
[36] Badawy SI, Narang AS, LaMarche K, Subramanian G,Varia SA. Mechanistic basis for the effects of process parameters on quality attributes in high shear wet granulation. Int J Pharm 2012;439(1):324–33.
[37] Knight P, Johansen A, Kristensen H, Schaefer T, Seville J. An investigation of the effects on agglomeration of changing the speed of a mechanical mixer. Powder Technol2000;110(3):204–9.
[38] Ohno I, Hasegawa S, Yada S, Kusai A, Moribe K, Yamamoto K.Importance of evaluating the consolidation of granules manufactured by high shear mixer. Int J Pharm2007;338(1):79–86.
[39] Iskandarani B, Shiromani P, Clair J. Scale-up feasibility in high-shear mixers:determination through statistical procedures. Drug Dev Ind Pharm 2001;27(7):651–7.
[40] Ramaker J, Jelgersma MA, Vonk P, Kossen N. Scale-down of a high-shear pelletisation process:flow profile and growth kinetics. Int J Pharm 1998;166(1):89–97.
[41] Adolfsson A?, Nystr?m C. Tablet strength, porosity, elasticity and solid state structure of tablets compressed at high loads.Int J Pharm 1996;132(1):95–106.
[42] Osei-Yeboah F, Zhang M, Feng Y, Sun CC. A formulation strategy for solving the overgranulation problem in high shear wet granulation. J Pharm Sci 2014;103(8):2434–40.
[43] Sun CC. A classification system for tableting behaviors of binary powder mixtures. Asian J Pharm Sci 2016;11(4):486–91.
[44] Thapa P, Lee AR, Choi DH, Jeong SH. Effects of moisture content and compression pressure of various deforming granules on the physical properties of tablets. Powder Technol 2017;310:92–102.
[45] Basalious EB, Shawky N, Badr-Eldin SM. SNEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I:development and optimization.Int J Pharm 2010;391(1):203–11.
[46] Tung NT, Hung MV, Vo XM, Nguyen TH, Pham TMH.Formulation optimization of orally disintegrating tablets containing solid dispersion of felodipine and hydroxypropyl methylcellulose using face-centered central composite design. J Pharm Investig 2014;44(2):111-8.
[47] Roopwani R, Buckner IS. Understanding deformation mechanisms during powder compaction using principal component analysis of compression data. Int J Pharm2011;418(2):227–34.
[48] Rajalahti T, Kvalheim OM. Multivariate data analysis in pharmaceutics:a tutorial review. Int J Pharm2011;417(1):280–90.
[49] Cui Y, Song X, Chuang K, et al. Variable selection in multivariate modeling of drug product formula and manufacturing process. J Pharm Sci 2012;101(12):4597–607.
[50] Paul S, Taylor LJ, Murphy B, et al. Powder properties and compaction parameters that influence punch sticking propensity of pharmaceuticals. Int J Pharm2017;521(1):374–83.