Investigating the Effect of APAP Crystals on Tablet Behavior Manufactured by Direct Compression.

In this work, the effect of API's (Active Pharmaceutical Ingredient) shape and size on tablet characteristics is investigated for high API dose formulation manufactured by direct compression. Three different classes of APAP (acetaminophen) are selected, and tablets are produced in both single and batch processes. After performing and comparing comprehensive series of standard characterization tests including hardness, dissolution, disintegration, and friability on the tablets, the test results show the relation between the quality of APAP tablets and the shape and size of the crystals. We also investigate the effect of scaling up the manufacturing process (from single to batch) by evaluating dosage uniformity and possibility of segregation in blends. The results indicate a strong interaction between manufacturing parameters such as speed and scale of production to API crystal size and shape. This places crystal properties in the critical parameter set that requires tracking and monitoring in order to maintain consistent tablet properties in high-dose formulation continuous manufacturing operations.

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.

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.

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.

Investigating the applicability of inverse gas chromatography to binary powdered systems: an application of surface heterogeneity profiles to understanding preferential probe-surface interactions.

The aim of this study was to investigate the applicability of surface energy characterization tools such as inverse gas chromatography for the analysis of binary systems. Drug substance was coated with two grades of silicon dioxide and the surface energy characteristics determined using a surface energy analyser. The results demonstrated that the measured dispersive surface energy of such intermediate samples were as a consequence of probe interactions with both constituent components, however, the degree and order of interaction with each species was related to surface energy heterogeneity and surface availability. A method to predict the degree of probe-surface preferentiality within the intermediate samples was applied to the data, demonstrating to closely match the measured data whilst suggesting notable differences in probe-surface preferentiality. Specific probe interactions were also assessed and the results suggested that probe surface preferentiality was not equivalent to that of the dispersive probes, possibly due to differences in ranges of the dispersive/specific forces. An equivalent physically mixed sample was analysed and the results demonstrated that the measured heterogeneity curve mirrored that of the pure drug substance suggesting that the driver for probe interaction is different for the physically mixed and the coated intermediate samples.

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.

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.

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.