Exploring the relationship between bulk Young's Modulus of materials and milling efficiency during wet bead milling of pharmaceutical compounds.

Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical Ingredient (API) is reduced in a liquid vehicle via grinding. A common challenge observed during WBM is long milling time to achieve target particle size, resulting in poor milling efficiency. The objective of this work was to identify potential API attributes predictive of milling efficiency during WBM. In this study, physical and mechanical properties of nine APIs were characterized. Formulations with these APIs were manufactured using WBM. Bulk Young's Modulus was identified to have a significant influence on the rate of particle attrition. The rank order of Young's Moduli of the APIs was consistent with that of milling efficiency, estimated by an empirical function defined in this study called Milling Resistance (ϕ), representing the holistic impact of milling time, tip speed, bead loading, and batch to chamber volume ratio. The identification of such intrinsic material properties, which provide an early evaluation of potential manufacturing risks, is beneficial to product development, as these assessments can be performed with limited quantities of materials and help identify and design out scale-up challenges.

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

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.

Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study.

Daprodustat, an orally bioavailable hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease. Part A of this 2-part, randomized, double-blind, single-dose, cross-over study (NCT04640311) compared pharmacokinetic properties of a single oral dose of daprodustat 4 mg tablets manufactured via twin-screw wet granulation (process 1) to 2 sets of 4 mg tablets manufactured via high-shear wet granulation (process 2), to assess the impact of different dissolution profiles on pharmacokinetics. Part B assessed the bioequivalence of daprodustat tablets manufactured via process 1 with tablets manufactured via process 2 at 5 different dose strengths (1, 2, 4, 6, and 8 mg). In part A, mean plasma concentrations of daprodustat were comparable over a 24-hour period despite differences in manufacturing processes and dissolution profiles. In part B, the 90% confidence intervals of the ratios of the least squared means for area under the concentration-time curve and maximum observed plasma concentration fell within the 0.8-1.25 bioequivalence range for all doses, except for maximum observed plasma concentration at 8 mg. A prespecified sensitivity analysis jointly assessing all doses showed bioequivalence for all doses tested. No new safety concerns for daprodustat were identified.

Origin of two modes of non-isothermal crystallization of glasses produced by milling.

PURPOSE: To mechanistically explain the origin of two distinct non-isothermal crystallization modes, single-peak (unimodal) and two-peak (bimodal), of organic glasses. METHODS: Glasses of ten organic molecules were prepared by melt-quenching and cryogenic milling of crystals. Non-isothermal crystallization of glasses was monitored using differential scanning calorimetry and powder X-ray diffractometry. RESULTS: The non-isothermal crystallization of glass, generated by milling, is either unimodal or bimodal, while that of melt-quenched glass without being milled is always unimodal. The mode of crystallization of amorphous phase depends on the relative position of the crystallization onset (T ( c )) with respect to glass transition temperature (T ( g )), and can be explained by a surface crystallization model. Bimodal crystallization event is observed when T ( c ) is below or near T ( g ), due to the fast crystallization onset at milled glass surfaces. Unimodal crystallization is observed when T ( c ) is well above T ( g ). We have verified this model by intentionally inducing flip between the two crystallization modes for several compounds through manipulating glass surface area and T ( c ). CONCLUSIONS: The two modes of crystallization of organic glasses is a result of the combined effects of faster surface crystallization and variation in specific surface area by milling.

Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression.

Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process.

DEM based computational model to predict moisture induced cohesion in pharmaceutical powders.

Pharmaceutical powder flow can alter significantly based on the exposed humidity conditions, and lack of computational models to predict the same may undermine process development, optimization, and scale-up performances. A Discrete Element Model (DEM) is proposed to predict the effects of humidity on pharmaceutical powder flow by altering the cohesive forces based on granular bond numbers in simple hopper geometries. Experiments analogous to the simulations are further performed for three commonly used pharmaceutical excipients at 20%, 40% and 60% RH. The equivalent DEM based bond numbers to predict the powder flow tendencies are in good accordance with the experimental results and can be a useful tool to predict the outcomes of different pharmaceutical processing techniques at various humidity conditions.

Multivariate monitoring for the industrialisation of a continuous wet granulation tableting process.

The pharmaceutical industry is undergoing a significant change in product development and manufacturing strategies with the progressive shift from batch to continuous processes. These typically feature vast volumes of data generated by the numerous sensors connected to several unit operations running over the period of several hours or even days and that demand the application of increasingly efficient tools for process understanding, monitoring and control. This paper describes the use of multivariate statistical process modeling by means of chemometric methods to monitor the continuous wet granulation tableting process for a drug product currently under development. Models are tailored to the different units that make up the continuous tableting line, from material feeding and granulation up to tablet compression, where the solutions devised reflect the different dynamics of each unit and are used as maintenance and intervention tools to optimise manufacturing and associated operations retrospectively as well as in real-time, as part of the product industrialisation programme.

Sticking and Picking in Pharmaceutical Tablet Compression: An IQ Consortium Review.

Sticking and picking during tablet manufacture has received increasing interest recently, as it causes tablet defects, downtime in manufacturing, and yield losses. The capricious nature of the problem means that it can appear at any stage of the development cycle, even when it has been deemed as low risk by models, tests, and previous experience. In many cases, the problem manifests when transferring the process from one manufacturing site to another. Site transfers are more common now than in previous times because of the multinational nature of drug product manufacturing and the need for redundancy in manufacturing networks. Sticking is a multifactorial problem, so one single "fix" is unlikely to solve it completely, and "solutions" addressing one problem may exacerbate another. A broad-based strategy involving the API, formulation, tablet tooling, and the manufacturing process is the most likely approach to provide a robust and lasting solution. When faced with a sticking problem for the first or subsequent time, the formulator should address, in a structured way, a range of possible causes and remedies. In this article, we focus on current research and practice; on some of the common causes of sticking; mitigation and resolution strategies and solutions; and possible future directions in research.

Effect of heating rate and kinetic model selection on activation energy of nonisothermal crystallization of amorphous felodipine.

The nonisothermal crystallization kinetics of amorphous materials is routinely analyzed by statistically fitting the crystallization data to kinetic models. In this work, we systematically evaluate how the model-dependent crystallization kinetics is impacted by variations in the heating rate and the selection of the kinetic model, two key factors that can lead to significant differences in the crystallization activation energy (Ea ) of an amorphous material. Using amorphous felodipine, we show that the Ea decreases with increase in the heating rate, irrespective of the kinetic model evaluated in this work. The model that best describes the crystallization phenomenon cannot be identified readily through the statistical fitting approach because several kinetic models yield comparable R(2) . Here, we propose an alternate paired model-fitting model-free (PMFMF) approach for identifying the most suitable kinetic model, where Ea obtained from model-dependent kinetics is compared with those obtained from model-free kinetics. The most suitable kinetic model is identified as the one that yields Ea values comparable with the model-free kinetics. Through this PMFMF approach, nucleation and growth is identified as the main mechanism that controls the crystallization kinetics of felodipine. Using this PMFMF approach, we further demonstrate that crystallization mechanism from amorphous phase varies with heating rate.

Preparation and characterization of surface-engineered coarse microcrystalline cellulose through dry coating with silica nanoparticles.

A popular grade of microcrystalline cellulose (MCC) exhibits excellent tabletability, but marginal flowability for high-speed tableting operations. Accordingly, an enhancement in flowability, while preserving its tabletability, will make it a more useful excipient in pharmaceutical tablet formulations, especially for the direct compression process. In this work, we show that surface coating by silica nanoparticles, using either a dry comilling process or simple mechanical blending, is a valid strategy for achieving the goal. The effects of milling intensity, either the number of comilling cycles or blending time, and silica loading level have been evaluated. Results show that surface deposition of 0.1% silica nanoparticles substantially improves the flowability of this grade of MCC while preserving a significant portion of its tabletability. Higher silica loading leads to better flowability, but at the cost of reduced tabletability. However, even up to 2.0% silica deposition, its tabletability remains superior.

Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano-silica through comilling.

Poor flow properties hinder the easy handling of powders during industrial-scale processing. In this work, we show that powder flow can be substantially improved by reducing the cohesion of powders by coating them with nanosized guest particles. We further show that comilling is an efficient process for nanocoating. We have systematically investigated the effects of total number of comilling cycles (10-70 cycles) and silica loading (0-1.0 wt %) on the flow behavior of a highly cohesive and poorly flowing grade of microcrystalline cellulose powder (Avicel PH105). Optimum flow enhancement has been achieved with 1.0 wt % silica loading at 40 comilling cycles. The flow properties of nanocoated Avicel PH105 are comparable to those of Avicel PH102, which exhibits adequate flowability for processing on a high-speed tablet press. Comilling is fast and suitable for continuous processing. It shows potential for addressing industrial powder handling problems caused by poor powder flow properties.