San Kiang

Modeling of Pan Coating Processes: Prediction of Tablet Content Uniformity and Determination of Critical Process Parameters

We developed an engineering model for predicting the active pharmaceutical ingredient (API) content uniformity (CU) for a drug product in which the active is coated onto a core. The model is based on a two-zone mechanistic description of the spray coating process in a perforated coating pan. The relative standard deviation (RSD) of the API CU of the coated tablets was found to be inversely proportional to the square root of the total number of cycles between the spray zone and drying zone that the tablets undergo. The total number of cycles is a function of the number of tablets in the drying zone, the spray zone width, the tablet velocity, the tablet number density, and the total coating time. The sensitivity of the RSD to various critical coating process parameters, such as pan speed, pan load, spray zone width, as well as tablet size and shape was evaluated. Consequently, the critical coating process parameters needed to achieve the desired API CU were determined. Several active film coating experiments at 50, 200, and 400 kg using various pan coaters demonstrated that good correlation between the model predictions and the experimental results for the API CU was achieved.

Raman spectroscopy for the determination of coating uniformity of tablets: assessment of product quality and coating pan mixing efficiency during scale-up

Spray coating is an important unit operation in the pharmaceutical industry. The quality, stability, safety, and performance of the final product depend largely on the amount and uniformity of coating applied. Raman spectroscopy is used to develop a multivariate quantitative model using tablets collected from different stages of coating. Subsequently, the calibration is used for the determination of coating progress in small-scale batches. The method developed is used as a process analytical technology tool to assess the desired product quality attributes in commercial scale equipment. Insight into the mixing efficiency is gained by examining intra-tablet variability using the Raman method.

Evaluation of Risk and Benefit in the Implementation of Near-Infrared Spectroscopy for Monitoring of Lubricant Mixing

On-line near-infrared spectroscopy (NIRS) was used to monitor lubricant blending to ensure the quality of the final dosage form. A quantitative multivariate NIR model was developed using different lubricant concentration levels. Real-time model predictions correlated well with the expected lubricant concentration during blending, which allowed determination of blend quality. The significance of sensor location on the blender at different fill levels was evaluated. The capability of this application was further assessed by real-time study of blending dynamics under varying process conditions and raw material attributes. The response of the developed NIR method to sudden spikes in analyte concentration, changes in raw material attributes, and perturbations to standard mixing procedures was evaluated. This study allows an understanding of risk factors associated with the implemented technology, and its ability to accurately monitor the process events. Furthermore, it highlights the importance of proper selection of processing conditions and raw material attributes to improve process robustness.

The Measurement of Spray Quality for Pan Coating Processes

AbstractIn this study, we describe the use of an innovative imaging system to measure and control the effect of nozzle operating parameters on the characteristics of a spray. These characteristics, including spray pattern, droplet size distribution, and droplet velocity, define the quality of the spray. They can have significant impact on the efficiency of the pan coating process and the quality of the coat. Suspensions of different composition were used in this study, and the authors demonstrated that the spray characteristics can be controlled with this approach.The main conclusions from this study were: 1.The AA/Spray (atomization air/spray rate) and AA/PA (atomization air/pattern air) mass flow ratios were the key parameters that affect spray characteristics. Although viscosity can impact the spray, there was minimal impact within the viscosity range tested in this study.2.With proper selection of the AA/Spray and AA/PA mass flow ratios, it was possible to generate sprays with consistent spatial distributions of volume flux with minimal variations of mean droplet size over the range of coating suspensions and spray rates studied. Spray characterization can be a powerful tool for exploring and establishing the design space of nozzles operation in the pan coating process. When scaling or transferring a spray coating process, the focus should be on maintaining consistent spray qualities rather than limiting nozzle operating parameters to a range. This approach embraces the FDA concept of process analytical technology (PAT) and design space (FDA, Guidance for industry PAT—A framework for innovative pharmaceutical development, manufacturing, and quality assurance, 2004) for science-based operation flexibility.

Experimental and model-based approaches to studying mixing in coating pans

The focus of this study was the determination of mixing patterns and rates inside a cylindrical coating pan. The research for this study was divided into two parts. The first part examined the mixing pattern and the movement of tablets inside of a coating pan experimentally. The second part consisted of using a DEM (Discrete Element Model) simulation to evaluate mixing in the coating pan in silico. Mixing was investigated as a function of the rate of rotation of the pan and the number of revolutions. Mixing rates were measured in two directions – axial – from the front of the unit to the back of the unit along its axis and radial/angular – in the plane orthogonal to its axis. Radial/angular mixing was faster than axial mixing – the coating pan was found to be well-mixed across the axis within 2–8 revolutions as compared to 16–32 revolutions needed for the pan to be well-mixed along the axis. The DEM simulation used for this study is capable of predicting how fast the tablets mix in the coating pan. It does so by explicitly modeling the motion of individual tablets in the unit. Model predictions were verified by comparing the simulated mixing in the coating pan to the experiments. The simulated mixing process is found to be slightly slower than the experimentally observed mixing, which means that the simulations give a conservative estimate of mixing rates. The model can also be used to calculate the residence time distribution of the tablets in a spray zone of a given area.

Use of enthalpy and Gibbs free energy to evaluate the risk of amorphous formation

The control of crystalline and amorphous phases is important during the development of a new drug candidate. Our approach begins with an understanding of the thermodynamics of these two phases. We have developed a quantitative yet practical work flow consisting of three steps towards the analysis of the risk of amorphous material formation. First, we derive the thermodynamic equations to calculate the enthalpy, Gibbs free energy, and the solubility of each phase and their differences as a function of temperature. The enthalpy for each crystalline drug substance at its melting point is selected as the reference state to enable a consistent approach for all analysis. Second, we use data from DSC measurements and the derived thermodynamic equations to construct the enthalpy, Gibbs free energy and solubility diagrams so as to compare the characteristics of these two phases. Finally, we use the results of these calculations to evaluate the potential risk of crystalline-to-amorphous phase conversion during processing of either the drug substance or the drug product. In addition, the impact of amorphous formation on solubility is evaluated. Two drug candidates are used to illustrate this workflow for risk analysis.

A novel co-processing method to manufacture an API for extended release formulation via formation of agglomerates of active ingredient and hydroxypropyl methylcellulose during crystallization

Abstract A novel process for generating agglomerates of active pharmaceutical ingredient (API) and polymer by swelling the polymer in a water/organic mixture has been developed to address formulation issues resulting from a water sensitive, high drug load API with poor powder properties. Initially, the API is dissolved in water, following which hydroxypropyl methylcellulose (HPMC) is added, resulting in the imbibing of water, along with the dissolved API, into the HPMC matrix. The addition of acetone and isopropyl acetate (anti-solvents) then causes the API to crystallize inside and on the surface of HPMC agglomerates. The process was scaled up to 20 kg scale. The agglomerates of API and HPMC generated by this process are ∼350 µm diameter, robust, and have significantly better flow than the API as measured by Erweka flow testing. These agglomerates exhibit improved bulk density, acceptable chemical stability, and high compressibility. The agglomerates process well through roller compaction and tableting, with no flow or sticking issues. This process is potentially adaptable to other APIs with similar attributes.