Analysis of heat generation during the production of drug nanosuspensions in a wet stirred media mill

Guner, Gulenay; Seetharaman, Natasha; Elashri, Sherif; Mehaj, Mirsad; Bilgili, Ecevit

doi:10.1016/j.ijpharm.2022.122020

Cited by 16 publications

(11 citation statements)

References 55 publications

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“…Bead size can be an important process parameter as it may provide combined advantages of faster breakage [ 21 , 50 , 64 ], lower heat generation rate [ 65 , 66 , 67 ], and lower media wear [ 21 , 64 ]. However, its impact on the breakage rate may be more subtle because it has counteracting microhydrodynamic trends where smaller beads capture drug particles more frequently but apply less stress upon contact [ 20 , 60 ].…”

Section: Resultsmentioning

confidence: 99%

“…4.1.5. Impact of Temperature Temperature during milling varies over time and is influenced by the process parameters [65][66][67], which may have an impact on the particle size evolution. To investigate this hypothesis, we proposed an Arrhenius function for the j th size quantile that accounts for the temperature dependency, i.e., Kt j (see Section 3.2.2).…”

Section: Impact Of Bead Sizementioning

confidence: 99%

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Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions

Clancy,

Guner,

Chattoraj

et al. 2024

Pharmaceutics

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This study aimed to develop a practical semi-mechanistic modeling framework to predict particle size evolution during wet bead milling of pharmaceutical nanosuspensions over a wide range of process conditions and milling scales. The model incorporates process parameters, formulation parameters, and equipment-specific parameters such as rotor speed, bead type, bead size, bead loading, active pharmaceutical ingredient (API) mass, temperature, API loading, maximum bead volume, blade diameter, distance between blade and wall, and an efficiency parameter. The characteristic particle size quantiles, i.e., x10, x50, and x90, were transformed to obtain a linear relationship with time, while the general functional form of the apparent breakage rate constant of this relationship was derived based on three models with different complexity levels. Model A, the most complex and general model, was derived directly from microhydrodynamics. Model B is a simpler model based on a power-law function of process parameters. Model C is the simplest model, which is the pre-calibrated version of Model B based on data collected from different mills across scales, formulations, and drug products. Being simple and computationally convenient, Model C is expected to reduce the amount of experimentation needed to develop and optimize the wet bead milling process and streamline scale-up and/or scale-out.

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Section: Resultsmentioning

confidence: 99%

Section: Impact Of Bead Sizementioning

confidence: 99%

Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions

Clancy,

Guner,

Chattoraj

et al. 2024

Pharmaceutics

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“…Therefore, it is important to identify the material attributes of the drug substance that may be critical to a temperature rise, requiring temperature control by the adjustment of the process parameters of the milling process, as demonstrated by Guner et al In their study, it was shown that the rate of the temperature increase in the suspension during a wet stirred media milling process depends on the selected process parameters of the stirrer speed, bead loading and bead size [ 43 ]. When selecting process conditions with lower energetic levels (the lowest stirrer speed, lowest bead loading and smallest beads), an overall temperature rise of 6 °C over 60 min was observed for the suspension [ 43 ]. In contrast, high energetic conditions (the fastest stirrer speed, largest bead loading and largest beads) caused a temperature jump from 18 °C to 45 °C in 2 min [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…When selecting process conditions with lower energetic levels (the lowest stirrer speed, lowest bead loading and smallest beads), an overall temperature rise of 6 °C over 60 min was observed for the suspension [ 43 ]. In contrast, high energetic conditions (the fastest stirrer speed, largest bead loading and largest beads) caused a temperature jump from 18 °C to 45 °C in 2 min [ 43 ]. A helpful tool from a temperature rise perspective, designed in this study, is the thermal desirability score (TDS).…”

Section: Discussionmentioning

confidence: 99%

“…A helpful tool from a temperature rise perspective, designed in this study, is the thermal desirability score (TDS). The TDS rates a milling process on the basis of the temperature increase and the number of cycles—as excellent (corresponding to almost isothermal conditions), good, acceptable or poor [ 43 ]. Because the material attributes of IMQ, which has a high melting point (297–299 °C), features practically insolubility in water (also at elevated temperatures) and lacks known polymorphic forms with no change in the crystallinity of the drug before and after milling (see Figure S1 ), are uncritical for physicochemical instabilities, thanks to a temperature rise during milling, temperature control is not required.…”

Section: Discussionmentioning

confidence: 99%

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Quality by Design (QbD) Approach for a Nanoparticulate Imiquimod Formulation as an Investigational Medicinal Product

et al. 2023

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The present article exemplifies the application of the concept of quality by design (QbD) for the systematic development of a nanoparticulate imiquimod (IMQ) emulsion gel formulation as an investigational medicinal product (IMP) for evaluation in an academic phase-I/II clinical trial for the treatment of actinic keratosis (AK) against the comparator Aldara (EudraCT: 2015-002203-28). The design of the QbD elements of a quality target product profile (QTPP) enables the identification of the critical quality attributes (CQAs) of the drug product as the content of IMQ, the particle-size distribution, the pH, the rheological properties, the permeation rate and the chemical, physical and microbiological stability. Critical material attributes (CMAs) and critical process parameters (CPPs) are identified by using a risk-based approach in an Ishikawa diagram and in a risk-estimation matrix. In this study, the identified CPPs of the wet media ball-milling process’s milling time and milling speed are evaluated in a central composite design of experiments (DoEs) approach, revealing criticality for both factors for the resulting mean particle size, while only the milling time is significantly affecting the polydispersity. To achieve a mean particle size in the range of 300–400 nm with a minimal PdI, the optimal process conditions are found to be 650 rpm for 135 min. Validating the model reveals a good correlation between the predicted and observed values. Adequate control strategies were implemented for intermediate products as in-process controls (IPCs) and quality control (QC) tests of the identified CQAs. The IPC and QC data from 13 “IMI-Gel” batches manufactured in adherence to good manufacturing practice (GMP) reveal consistent quality with minimal batch-to-batch variability.

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Small-scale aqueous suspension preparation using dual centrifugation: the effect of process parameters on the sizes of drug particles

Zulbeari,

Lund,

Holm

2025

European Journal of Pharmaceutical Sciences

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Analysis of heat generation during the production of drug nanosuspensions in a wet stirred media mill

Cited by 16 publications

References 55 publications

Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions

Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions

Quality by Design (QbD) Approach for a Nanoparticulate Imiquimod Formulation as an Investigational Medicinal Product

Small-scale aqueous suspension preparation using dual centrifugation: the effect of process parameters on the sizes of drug particles

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