(139d) Thermal Analysis of the Wet Stirred Media Milling Process Used for the Production of Drug Nanoparticle Suspensions
AIChE Annual Meeting
2022
2022 Annual Meeting
Pharmaceutical Discovery, Development and Manufacturing Forum
Enabling Technologies: Progress in Tools and Technologies
Monday, November 14, 2022 - 1:33pm to 1:54pm
Nanocomposite formation has been of the most popular platform approaches in dissolution enhancement of poorly water-soluble drugs as the higher surface area and mass transfer coefficient of the nanoparticles can lead to faster dissolution than their micron-sized counterparts [1]. Wet stirred media milling (WSMM) has been the most preferred method for the manufacture and preparation of marketed drug nanocrystal-based products and nanocrystal suspensions in scientific studies [2]. The reason for this high demand for WSMM is that it has the potential of producing high drug-loaded, stable nanosuspensions while being a reproducible, scalable, solvent-free, and environmentally benign process [3]. On the other hand, if the process conditions are not selected carefully, WSMM can suffer from long cycle times, high energy consumption, and overheating problems [4].
In WSMM, like any other milling operation, only a small fraction of the mechanical energy spent on mixing the slurry is used to deform the drug particles [5]; most is eventually converted into heat through dissipative processes (viscous losses, inelastic bead collisions, etc.), which causes the temperature to rise during the milling. The occurrence of notable temperature rise required researchers to shut down the mill intermittently and cooled it without further milling [6, 7]. Nonetheless, temperature plays an important role and needs to be controlled during the WSMM of drug suspensions. First, the physical or chemical stability of a drug suspension could be susceptible to temperature [8, 9]. Drugs especially thermolabile drugs require stringent low-temperature control to avoid chemical degradation. Moreover, a polymer like hydroxypropyl cellulose (HPC), which is a commonly used steric stabilizer in drug nanosuspensions, has a lower critical solution temperature (LCST), a.k.a. clouding point temperature, of ~45 oC [10]. HPC may start precipitating out of aqueous solution at or above LCST, which may in turn cause physical destabilization of drug nanosuspensions. Also, a higher temperature during WSMM or storage could facilitate Ostwald ripening and growth of drug nanoparticles [11, 12]. In many industries where WSMM is used frequently such as ores, inkjet inks, ceramics, etc., a stringent low-temperature control is not needed as these materials do not have a risk of thermal degradation during the WSMM. In fact, for these materials, higher temperatures are likely to be tolerated as the viscosity and associated power consumption during the milling are lowered at higher temperatures. On the other hand, in the pharmaceutical industry, a stringent temperature control during the WSMM is required for the reasons mentioned above. Even though temperature control and heat dissipation are important for a WSMM process, it is interesting to note that the impact of process parameters on heat dissipation and temperature during the WSMM has not been investigated. We hypothesize that temperature is a strong function of the power consumption during the WSMM as observed during our previous study [13].
This study aims to examine the timewise evolution of the mill outlet temperature and chiller temperature as a function of intermittent milling and cooling time (if mill is shut down). Fenofibrate was used as the model drug and its stable suspension with HPC was prepared. The precursor suspensions were milled at three different stirrer speeds, bead loadings and bead sizes to explore their impact on the timewise evolution of temperature at the mill outlet. We aimed to keep the mill outlet temperature below 45 oC. The mill was shot down with continued cooling whenever the outlet temperature reached 45 oC, which led to multiple intermittent milling/cooling cycles. The fenofibrate particles were subjected to a total of 60 min milling; however, the actual cycle time was longer when multiple intermittent milling cycles followed by cooling were applied. The temperatures at the mill outlet and the chiller are recorded every minute or every 30 s, depending on the heat release rate (based on knowledge from exploratory experiments). After milling, the particle sizes were measured using laser diffraction. Also, densities and viscosities are determined to be used in Reynolds number calculations, which will be used for explaining the power–heat generation relationship. In order to identify any quantitative trend between the process conditions and the heat generation, specific times and temperatures were defined such as the maximum temperature, the temperature at 5 min of milling, and the time required to reach 25 oC, etc.
The figure shows examples of the temperature profile to give an overall idea, where the top figure corresponds to mill operation at the lowest energetic conditions, the middle figure to the medium energetic conditions, and the bottom figure to the highest energetic condition. It is clear that the temperature profiles changed drastically at different energetic (Pw: power consumption) levels. While the lowest Pw caused a 6 oC increase at the end of 60 min milling, the highest Pw caused a 28 oC jump in the temperature in around 2 min. After evaluating all specific times and specific temperatures (not shown for brevity here), the time required for the temperature to reach 22 oC and the temperature at 5 min. of milling were found to be the best measures to represent all dynamic data and a strong correlation between these measures and Pw was developed with R2~0.9. This correlation is important because if one can develop a correlation between the power number and the process conditions, one can make power predictions and then specific temperature predictions. Our experimental results have also pointed out that an increase in stirrer speed and/or bead loading led to significantly notable max. temperature and faster temperature rise, whereas the impact of bead size was relatively weak within the range studied. Overall, this study has provided the first thermal analysis of the WSMM process for nanomilling drug suspensions, demonstrating the criticality of process parameter selection to avoid any overheating or multiple mill shutdowns. We have also demonstrated the fundamental origin of reduced/restricted design space for drug suspension manufacturing due to limits imposed by the thermal effects due to high heat generation at the higher speeds/bead concentrations.
References
[1] A. Bhakay, M. Rahman, R.N. Dave, E. Bilgili, Bioavailability enhancement of poorly water-soluble drugs via nanocomposites: Formulationâ»processing aspects and challenges, Pharmaceutics, 10 (2018) 86.
[2] M. Li, M. Azad, R. Davé, E. Bilgili, Nanomilling of drugs for bioavailability enhancement: A holistic formulation-process perspective, Pharmaceutics, 2016.
[3] L. Peltonen, Design space and qbd approach for production of drug nanocrystals by wet media milling techniques, Pharmaceutics, 10 (2018) 104.
[4] E. Bilgili, G. Guner, Mechanistic modeling of wet stirred media milling for production of drug nanosuspensions, AAPS PharmSciTech, 22 (2020) 2.
[5] D. Eskin, O. Zhupanska, R. Hamey, B. Moudgil, B. Scarlett, Microhydrodynamic analysis of nanogrinding in stirred media mills, AIChE Journal, 51 (2005) 1346-1358.
[6] N. Parker, M. Rahman, E. Bilgili, Impact of media material and process parameters on breakage kinetics–energy consumption during wet media milling of drugs, European Journal of Pharmaceutics and Biopharmaceutics, 153 (2020) 52-67.
[7] G. Guner, D. Yilmaz, E. Bilgili, Kinetic and microhydrodynamic modeling of fenofibrate nanosuspension production in a wet stirred media mill, Pharmaceutics, 13 (2021) 1055.
[8] S. Verma, S. Kumar, R. Gokhale, D.J. Burgess, Physical stability of nanosuspensions: Investigation of the role of stabilizers on ostwald ripening, International Journal of Pharmaceutics, 406 (2011) 145-152.
[9] B. Van Eerdenbrugh, L. Froyen, J. Van Humbeeck, J.A. Martens, P. Augustijns, G. Van den Mooter, Drying of crystalline drug nanosuspensions—the importance of surface hydrophobicity on dissolution behavior upon redispersion, Eur. J. Pharm. Sci., 35 (2008) 127-135.
[10] Nisso- hydroxypropyl cellulose. Technical data sheet 2011.
[11] C. Konnerth, C. Damm, J. Schmidt, W. Peukert, Mechanical activation of trans-stilbene during wet grinding, Advanced Powder Technology, 25 (2014) 1808-1816.
[12] C. Knieke, M.A. Azad, R.N. Davé, E. Bilgili, A study of the physical stability of wet media-milled fenofibrate suspensions using dynamic equilibrium curves, Chemical Engineering Research and Design, 91 (2013) 1245-1258.
[13] G. Guner, M. Kannan, M. Berrios, E. Bilgili, Use of bead mixtures as a novel process optimization approach to nanomilling of drug suspensions, Pharmaceutical Research, 38 (2021) 1279-1296.
In WSMM, like any other milling operation, only a small fraction of the mechanical energy spent on mixing the slurry is used to deform the drug particles [5]; most is eventually converted into heat through dissipative processes (viscous losses, inelastic bead collisions, etc.), which causes the temperature to rise during the milling. The occurrence of notable temperature rise required researchers to shut down the mill intermittently and cooled it without further milling [6, 7]. Nonetheless, temperature plays an important role and needs to be controlled during the WSMM of drug suspensions. First, the physical or chemical stability of a drug suspension could be susceptible to temperature [8, 9]. Drugs especially thermolabile drugs require stringent low-temperature control to avoid chemical degradation. Moreover, a polymer like hydroxypropyl cellulose (HPC), which is a commonly used steric stabilizer in drug nanosuspensions, has a lower critical solution temperature (LCST), a.k.a. clouding point temperature, of ~45 oC [10]. HPC may start precipitating out of aqueous solution at or above LCST, which may in turn cause physical destabilization of drug nanosuspensions. Also, a higher temperature during WSMM or storage could facilitate Ostwald ripening and growth of drug nanoparticles [11, 12]. In many industries where WSMM is used frequently such as ores, inkjet inks, ceramics, etc., a stringent low-temperature control is not needed as these materials do not have a risk of thermal degradation during the WSMM. In fact, for these materials, higher temperatures are likely to be tolerated as the viscosity and associated power consumption during the milling are lowered at higher temperatures. On the other hand, in the pharmaceutical industry, a stringent temperature control during the WSMM is required for the reasons mentioned above. Even though temperature control and heat dissipation are important for a WSMM process, it is interesting to note that the impact of process parameters on heat dissipation and temperature during the WSMM has not been investigated. We hypothesize that temperature is a strong function of the power consumption during the WSMM as observed during our previous study [13].
This study aims to examine the timewise evolution of the mill outlet temperature and chiller temperature as a function of intermittent milling and cooling time (if mill is shut down). Fenofibrate was used as the model drug and its stable suspension with HPC was prepared. The precursor suspensions were milled at three different stirrer speeds, bead loadings and bead sizes to explore their impact on the timewise evolution of temperature at the mill outlet. We aimed to keep the mill outlet temperature below 45 oC. The mill was shot down with continued cooling whenever the outlet temperature reached 45 oC, which led to multiple intermittent milling/cooling cycles. The fenofibrate particles were subjected to a total of 60 min milling; however, the actual cycle time was longer when multiple intermittent milling cycles followed by cooling were applied. The temperatures at the mill outlet and the chiller are recorded every minute or every 30 s, depending on the heat release rate (based on knowledge from exploratory experiments). After milling, the particle sizes were measured using laser diffraction. Also, densities and viscosities are determined to be used in Reynolds number calculations, which will be used for explaining the power–heat generation relationship. In order to identify any quantitative trend between the process conditions and the heat generation, specific times and temperatures were defined such as the maximum temperature, the temperature at 5 min of milling, and the time required to reach 25 oC, etc.
The figure shows examples of the temperature profile to give an overall idea, where the top figure corresponds to mill operation at the lowest energetic conditions, the middle figure to the medium energetic conditions, and the bottom figure to the highest energetic condition. It is clear that the temperature profiles changed drastically at different energetic (Pw: power consumption) levels. While the lowest Pw caused a 6 oC increase at the end of 60 min milling, the highest Pw caused a 28 oC jump in the temperature in around 2 min. After evaluating all specific times and specific temperatures (not shown for brevity here), the time required for the temperature to reach 22 oC and the temperature at 5 min. of milling were found to be the best measures to represent all dynamic data and a strong correlation between these measures and Pw was developed with R2~0.9. This correlation is important because if one can develop a correlation between the power number and the process conditions, one can make power predictions and then specific temperature predictions. Our experimental results have also pointed out that an increase in stirrer speed and/or bead loading led to significantly notable max. temperature and faster temperature rise, whereas the impact of bead size was relatively weak within the range studied. Overall, this study has provided the first thermal analysis of the WSMM process for nanomilling drug suspensions, demonstrating the criticality of process parameter selection to avoid any overheating or multiple mill shutdowns. We have also demonstrated the fundamental origin of reduced/restricted design space for drug suspension manufacturing due to limits imposed by the thermal effects due to high heat generation at the higher speeds/bead concentrations.
References
[1] A. Bhakay, M. Rahman, R.N. Dave, E. Bilgili, Bioavailability enhancement of poorly water-soluble drugs via nanocomposites: Formulationâ»processing aspects and challenges, Pharmaceutics, 10 (2018) 86.
[2] M. Li, M. Azad, R. Davé, E. Bilgili, Nanomilling of drugs for bioavailability enhancement: A holistic formulation-process perspective, Pharmaceutics, 2016.
[3] L. Peltonen, Design space and qbd approach for production of drug nanocrystals by wet media milling techniques, Pharmaceutics, 10 (2018) 104.
[4] E. Bilgili, G. Guner, Mechanistic modeling of wet stirred media milling for production of drug nanosuspensions, AAPS PharmSciTech, 22 (2020) 2.
[5] D. Eskin, O. Zhupanska, R. Hamey, B. Moudgil, B. Scarlett, Microhydrodynamic analysis of nanogrinding in stirred media mills, AIChE Journal, 51 (2005) 1346-1358.
[6] N. Parker, M. Rahman, E. Bilgili, Impact of media material and process parameters on breakage kinetics–energy consumption during wet media milling of drugs, European Journal of Pharmaceutics and Biopharmaceutics, 153 (2020) 52-67.
[7] G. Guner, D. Yilmaz, E. Bilgili, Kinetic and microhydrodynamic modeling of fenofibrate nanosuspension production in a wet stirred media mill, Pharmaceutics, 13 (2021) 1055.
[8] S. Verma, S. Kumar, R. Gokhale, D.J. Burgess, Physical stability of nanosuspensions: Investigation of the role of stabilizers on ostwald ripening, International Journal of Pharmaceutics, 406 (2011) 145-152.
[9] B. Van Eerdenbrugh, L. Froyen, J. Van Humbeeck, J.A. Martens, P. Augustijns, G. Van den Mooter, Drying of crystalline drug nanosuspensions—the importance of surface hydrophobicity on dissolution behavior upon redispersion, Eur. J. Pharm. Sci., 35 (2008) 127-135.
[10] Nisso- hydroxypropyl cellulose. Technical data sheet 2011.
[11] C. Konnerth, C. Damm, J. Schmidt, W. Peukert, Mechanical activation of trans-stilbene during wet grinding, Advanced Powder Technology, 25 (2014) 1808-1816.
[12] C. Knieke, M.A. Azad, R.N. Davé, E. Bilgili, A study of the physical stability of wet media-milled fenofibrate suspensions using dynamic equilibrium curves, Chemical Engineering Research and Design, 91 (2013) 1245-1258.
[13] G. Guner, M. Kannan, M. Berrios, E. Bilgili, Use of bead mixtures as a novel process optimization approach to nanomilling of drug suspensions, Pharmaceutical Research, 38 (2021) 1279-1296.