Milling Operations in the Pharmaceutical Industry

Seibert, Kevin D.; Collins, Paul C.; Fisher, Elizabeth S.

doi:10.1002/9780470882221.ch19

Cited by 8 publications

(16 citation statements)

References 24 publications

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“…As such, great care is taken during the production of the API to achieve a targeted particle‐size distribution. Control of the API particle‐size distribution is traditionally achieved via batch crystallization processes or by milling . A significant amount of effort goes into designing crystallization and milling processes that consistently produce the desired API properties on scale‐up .…”

Section: Introductionmentioning

confidence: 99%

Scale‐up of agitated drying: Effect of shear stress and hydrostatic pressure on active pharmaceutical ingredient powder properties

et al. 2014

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Scale-up of agitated drying processes to minimize particle size changes in active pharmaceutical ingredients (API) can be challenging. Particle agglomeration or attrition problems due to agitated drying are often discovered on the initial scale-up from the lab to the plant. Traditional laboratory drying equipment has not successfully reproduced the degree of agglomeration or attrition observed at scale. This discrepancy may be attributed to the ability of particulate solids, such as crystalline API's to transfer stresses from the normal direction into the shearing direction. As batch size increases during scale-up, the compressive and shearing forces experienced by the API increase. To overcome this limitation, a modified laboratory setup was constructed which reproduces the range of hydrostatic pressures observed during scale-up. This work highlights the use of the modified setup to characterize the propensity for particle attrition to occur at different stages of the drying process by measuring impeller torque. Torque measurements of the API powder at different hydrostatic pressures revealed a behavior consistent with Coulomb's law of friction. The torque data obtained from these measurements were used to determine the bulk friction coefficient for API powder beds at different liquid content. Additionally, the amount of work done by the impeller blades was correlated to the degree of particle attrition observed. A workflow for assessing risk of API attrition at scale is described. Agitation conditions: 15 RPM for 60 min. (a) Torque profile, (b) Initial 300 s of the torque profile from Figures 3a, (c) particle-size distribution of API before agitation and after 7, 30, and 60 min of agitation. 410

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Section: Introductionmentioning

confidence: 99%

Scale‐up of agitated drying: Effect of shear stress and hydrostatic pressure on active pharmaceutical ingredient powder properties

et al. 2014

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“…The medicinal mechanochemistry field has expanded during the past few years, from the construction of novel crystalline structures − ,, to the development of innovative protocols for the synthesis of pharmacologically active compounds using biocatalysts. ,, Nevertheless, grinding and milling techniques have existed during most of pharmacy’s history . Furthermore, dry and wet milling, mixing, granulation, and tableting are some of the most commonly used techniques in the pharmaceutical field involving the use of mechanical force that, as exposed in this review, can induce useful modifications in the components of a substrate.…”

Section: Medicinal Mechanochemistry In the Battlefieldmentioning

confidence: 99%

“…121,129,131 and milling techniques have existed during most of pharmacy's history. 140 Furthermore, dry and wet milling, mixing, granulation, and tableting are some of the most commonly used techniques in the pharmaceutical field involving the use of mechanical force that, as exposed in this review, can induce useful modifications in the components of a substrate. Relevant studies of how mechanical force produced during the tableting process can modify the crystallinity or even change the crystalline form of a pharmaceutical active ingredient have been reported with notable results.…”

Section: Battlefieldmentioning

confidence: 99%

Mechanochemical and Mechanoenzymatic Synthesis of Pharmacologically Active Compounds: A Green Perspective

Pérez‐Venegas

Juaristi

2020

ACS Sustainable Chem. Eng.

148

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Recently, the application of mechanochemical strategies in organic synthesis has attracted the attention of both the academic and industrial chemical communities. The high efficiency and low environmental impact of processes performed by mechanical activation has positioned mechanical methods among salient green techniques since it allows the accomplishment of most sustainable chemistry principles. In particular, mechanochemistry has been used as a tool for the synthesis of active pharmaceutical ingredients via chemical synthesis or through biocatalytic protocols using enzymes with outstanding results, while simultaneously increasing the efficiency and sustainability of the process. In this regard, the main purpose of the present perspective is to summarize current developments of mechanochemical and mechanoenzymatic approaches in the synthesis of pharmacologically active compounds. The importance of these techniques in the so-called medicinal mechanochemistry field will be highlighted.

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“…It has the potential to strongly modify the particle size and shape, either during or after a crystallization step, which can increase the efficiency of various downstream unit operations and improve important quality attributes of the final product. For instance, milling can enhance bioavailability, tablet content uniformity, and powder compactability. , Wet milling is often employed to produce narrow crystal size distributions without altering the crystallinity of the solids. Dry milling techniques can have several disadvantages, such as higher cost, generation of lattice defects, and amorphization, to name a few. − …”

Section: Introductionmentioning

confidence: 99%

Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. III. Wet Milling

Rajagopalan

Bötschi

Morari

et al. 2019

Crystal Growth & Design

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Several operating and control strategies with the purpose of manipulating the size and shape of crystals exhibiting needle-like morphology are presented using an ex situ wet mill as the actuator. A model-based operating policy and different model-free controllers are discussed. These controllers were coupled with an online particle size and shape monitoring tool. First, the attainable region in the size and shape space for a wet milling operation was evaluated in a simulation framework using a multidimensional population balance model describing the breakage phenomenon. Second, the operating and control strategies were tested experimentally in a lab-scale setup using two different milling configurations and two different compounds, namely, β L-glutamic acid and γ D-mannitol. The goal of the experiments was to drive various seed populations of the two compounds to several target average lengths in the size and shape space. It was observed that the modelbased operating policy, run without any feedback action, was not able to achieve this goal for arbitrary seed populations. The model-free controllers incorporating feedback were able to do so without relying on any multidimensional breakage model. These controllers enable the robust operation of wet milling stages in complex crystal size and shape modification processes.

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Milling Operations in the Pharmaceutical Industry

Cited by 8 publications

References 24 publications

Scale‐up of agitated drying: Effect of shear stress and hydrostatic pressure on active pharmaceutical ingredient powder properties

Scale‐up of agitated drying: Effect of shear stress and hydrostatic pressure on active pharmaceutical ingredient powder properties

Mechanochemical and Mechanoenzymatic Synthesis of Pharmacologically Active Compounds: A Green Perspective

Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. III. Wet Milling

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