Particle Size of Drug Substance and Product Content Uniformity—Theoretical Considerations

Johnson, Kevin C.

doi:10.1002/9780470386361.ch3

Cited by 2 publications

(2 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…e 3μþ13:5σ 2 s ð15Þ While closed-form statistical approaches such as the above exist, computational models have been used to model the stochastic process of particle-level sampling from a randomly mixed blend of varying properties. Zhang and Johnson [80] and Johnson [81] proposed deterministic models for sampling from a particle size distribution to assess content uniformity. Huang and Ku [82] offered a true Monte Carlo approach utilizing Poisson sampling across all particle size fractions, demonstrating that lognormal distributions showing skew can yield significant deviations from the normality assumption.…”

Section: Quantifying Mixednessmentioning

confidence: 99%

Direct Compaction Drug Product Process Modeling

et al. 2022

View full text Add to dashboard Cite

Most challenges during the development of solid dosage forms are related to the impact of any variations in raw material properties, batch size, or equipment scales on the product quality and the control of the manufacturing process. With the ever pertinent restrictions on time and resource availability versus heightened expectations to develop, optimize, and troubleshoot manufacturing processes, targeted and robust science-based process modeling platforms are essential. This review focuses on the modeling of unit operations and practices involved in batch manufacturing of solid dosage forms by direct compaction. An effort is made to highlight the key advances in the past five years, and to propose potentially beneficial future study directions.

show abstract

Section: Quantifying Mixednessmentioning

confidence: 99%

Direct Compaction Drug Product Process Modeling

et al. 2022

View full text Add to dashboard Cite

show abstract

“…This step transforms loose drug crystals or active pharmaceutical ingredients (API) into granules that exhibit better flowability, compressibility, and content uniformity for subsequent portioning and tableting. , Prior to granulation, drug crystals are often blended with various excipients (functional inactive substances added to the formulation) to either protect the active drug from moisture, modify drug dissolution, or act as a binder for the final product . Industrially, content uniformity at the individual granule level can be challenging due to the difficulty of obtaining homogeneous drug powder blends for granulation; , powder blend uniformity is highly dependent on drug crystal and excipient powder size and shape, bulk density, and adhesive or cohesive forces between different compounds within the mixture . Kawashima et al introduced the concept of spherical crystallization nearly three decades ago; this is a particularly facile process of granulation, in which spherical crystal agglomerates are directly formed during crystallization via the introduction of a bridging liquid or by conducting antisolvent crystallization within transient droplets (quasi emulsions) formed from miscible solvent pairs using high shear and agitation. , The main challenge of the aforementioned methods when conducted in agitated vessels is the coarse control over particle sizes, as the operation is sensitive to multiple scale-up factors such as mixing efficiency, impeller and vessel geometry, and inlet configuration.…”

Section: Introductionmentioning

confidence: 99%

Microfluidic Extractive Crystallization for Spherical Drug/Drug-Excipient Microparticle Production

Yeap

Acevedo

2019

Org. Process Res. Dev.

View full text Add to dashboard Cite

Granulation is a common manufacturing step for pharmaceutical drug products, which improves powder flowability, compactibility, and ensures tablet content uniformity. Granules of uniform content can conventionally be challenging to obtain due to powder segregation and mixing issues prior to granulation. Spherical crystallizationa method where drug crystals are directly formed into spherical granulesis a promising way to overcome issues with mixing and form granules with uniform content. However, a common challenge of existing quasi emulsion solvent diffusion or solvent extraction methods for spherical crystallization involving miscible solvents in stirred batch vessels is the coarse control over particles sizes, as they are sensitive to multiple scale-up factors (mixing efficiency, impeller and vessel geometry, inlet configuration). This limits the method in terms of content uniformity, which in turn limits the extent to which granules with tunable dissolution profiles can be created. Here, we propose a method for the formation of monodisperse drug-excipient microparticles with tunable release profiles via microfluidic spherical extractive crystallization using drug and excipient-loaded ethyl acetate-in-water emulsions. Monodisperse droplets are generated using microfluidics, and droplet saturation via solvent extraction leads to eventual and direct monodisperse spherical particle formation within minutes. We demonstrate this method using ethyl acetate droplets loaded with naproxen or naproxen and ethyl cellulose, as a hydrophobic drug and drug-excipient model system, respectively, and obtained monodisperse spherical microparticles in both cases. Lastly, preliminary investigations of in vitro drug release from a range of microparticles made from droplets containing different naproxen–ethyl cellulose ratios displayed clear differences in the release profiles. When coupled with microfluidic droplet generators that operate at high volumetric throughputs, this method has the potential to be applied in continuous manufacturing platforms for the production of monodisperse spherical drug particles or drug-excipient composites with excellent content uniformity and tunable release profiles at a kilogram per day scale throughput.

show abstract

Particle Size of Drug Substance and Product Content Uniformity—Theoretical Considerations

Cited by 2 publications

References 5 publications

Direct Compaction Drug Product Process Modeling

Direct Compaction Drug Product Process Modeling

Microfluidic Extractive Crystallization for Spherical Drug/Drug-Excipient Microparticle Production

Contact Info

Product

Resources

About