Roller compaction process development and scale up using Johanson model calibrated with instrumented roll data.

Roller compaction is a dry granulation process used to convert powder blends into free flowing agglomerates. During scale up or transfer of roller compaction process, it is critical to maintain comparable ribbon densities at each scale in order to achieve similar tensile strengths and subsequently similar particle size distribution of milled material. Similar ribbon densities can be reached by maintaining analogous normal stress applied by the rolls on ribbon for a given gap between rolls. Johanson (1965) developed a model to predict normal stress based on material properties and roll diameter. However, the practical application of Johanson model to estimate normal stress on the ribbon is limited due to its requirement of accurate estimate of nip pressure i.e. pressure at the nip angle. Another weakness of Johanson model is the assumption of a fixed angle of wall friction that leads to use of a fixed nip angle in the model. To overcome the above mentioned limitations, we developed a novel approach using roll force equations based on a modified Johanson model in which the requirement of pressure value at nip angle was eliminated. An instrumented roll on WP120 roller compactor was used to collect normal stress data measured at three locations across the width of a roll (P1, P2, P3), as well as gap and nip angle data on ribbon for placebo and various active blends along with corresponding process parameters. The nip angles were estimated directly using experimental pressure profile data of each run. The roll force equation of Johanson model was validated using normal stress, gap, and nip angle data of the placebo runs. The calculated roll force values compared well with those determined from the roll force equation provided for the Alexanderwerk(®) WP120 roller compactor. Subsequently, the calculation was reversed to estimate normal stress and corresponding ribbon densities as a function of gap and RFU (roll force per unit roll width). A placebo model was developed and calibrated using a subset of placebo run data obtained on WP120. The roll force values were calculated using vendor supplied equation. The nip angle was expressed as a function of gap and RFU. The nip angle, gap and RFU were used in a new roll force equation to estimate normal stress P2 at the center of the ribbon. Using ratios P1/P2 and P3/P2 from the calibration data set, P1 and P2 were estimated. The ribbon width over which P1, P2, and P3 are effective was determined by minimizing sum square error between the model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the placebo runs compared well with the experimental data. The placebo model also predicted with reasonable accuracy the ribbon densities of active A, B, and C blends prepared at various combinations of process parameters. The placebo model was then used to calculate scale up parameters from WP120 to WP200 roller compactor. While WP120 has a single screw speed, WP200 is equipped with a twin feed screw system. A limited number of roller compaction runs on WP200 was used as a calibration set to determine normal stress profile across ribbon width. The nip angle equation derived from instrumented roll data collected on WP120 was applied to estimate nip angles on WP200 at various processing conditions. The roll force values calculated from vendor supplied equation and the nip angle values were used in roll force equation to estimate normal stress P2 at the tip of the feed screws. Based on feed screw design, it was assumed that the normal stress at the center of the ribbon was equal to those calculated at the tip of the feed screws. The ratio of normal stress at the edge of the ribbon Pe to the normal stress P2 at the feed screw tip was optimized to minimize sum square error between model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the batches prepared on WP200 compared well with the experimental data thus indicating success of the scale up procedure. For the demonstration purpose, the model was also calibrated using instrumented roll data of active C batches. This would be applicable when sufficient amount of API is available or placebo model cannot predict ribbon density of active batches.

An evaluation of process parameters to improve coating efficiency of an active tablet film-coating process.

Effects of material and manufacturing process parameters on the efficiency of an aqueous active tablet film-coating process in a perforated pan coater were evaluated. Twenty-four batches representing various core tablet weights, sizes, and shapes were coated at the 350-500 kg scale. The coating process efficiency, defined as the ratio of the amount of active deposited on tablet cores to the amount of active sprayed, ranged from 86 to 99%. Droplet size and velocity of the coating spray were important for an efficient coating process. Factors governing them such as high ratios of the suspension spray rate to atomization air flow rate, suspension spray rate to pattern air flow rate, or atomization air flow rate to pattern air flow rate improved the coating efficiency. Computational fluid dynamics modeling of the droplets showed that reducing the fraction of the smaller droplets, especially those smaller than 10 µm, resulted in a marked improvement in the coating efficiency. Other material and process variables such as coating suspension solids concentration, pan speed, tablet velocity, exhaust air temperature, and the length of coating time did not affect the coating efficiency profoundly over the ranges examined here.

Instrumented roll technology for the design space development of roller compaction process.

Instrumented roll technology on Alexanderwerk WP120 roller compactor was developed and utilized successfully for the measurement of normal stress on ribbon during the process. The effects of process parameters such as roll speed (4-12 rpm), feed screw speed (19-53 rpm), and hydraulic roll pressure (40-70 bar) on normal stress and ribbon density were studied using placebo and active pre-blends. The placebo blend consisted of 1:1 ratio of microcrystalline cellulose PH102 and anhydrous lactose with sodium croscarmellose, colloidal silicon dioxide, and magnesium stearate. The active pre-blends were prepared using various combinations of one active ingredient (3-17%, w/w) and lubricant (0.1-0.9%, w/w) levels with remaining excipients same as placebo. Three force transducers (load cells) were installed linearly along the width of the roll, equidistant from each other with one transducer located in the center. Normal stress values recorded by side sensors and were lower than normal stress values recorded by middle sensor and showed greater variability than middle sensor. Normal stress was found to be directly proportional to hydraulic pressure and inversely to screw to roll speed ratio. For active pre-blends, normal stress was also a function of compressibility. For placebo pre-blends, ribbon density increased as normal stress increased. For active pre-blends, in addition to normal stress, ribbon density was also a function of gap. Models developed using placebo were found to predict ribbon densities of active blends with good accuracy and the prediction error decreased as the drug concentration of active blend decreased. Effective angle of internal friction and compressibility properties of active pre blend may be used as key indicators for predicting ribbon densities of active blend using placebo ribbon density model. Feasibility of on-line prediction of ribbon density during roller compaction was demonstrated using porosity-pressure data of pre-blend and normal stress measurements. Effect of vacuum to de-aerate pre blend prior to entering the nip zone was studied. Varying levels of vacuum for de-aeration of placebo pre blend did not affect the normal stress values. However, turning off vacuum completely caused an increase in normal stress with subsequent decrease in gap. Use of instrumented roll demonstrated potential to reduce the number of DOE runs by enhancing fundamental understanding of relationship between normal stress on ribbon and process parameters.

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.

Database management systems for process safety.

Several elements of the process safety management regulation (PSM) require tracking and documentation of actions; process hazard analyses, management of change, process safety information, operating procedures, training, contractor safety programs, pre-startup safety reviews, incident investigations, emergency planning, and compliance audits. These elements can result in hundreds of actions annually that require actions. This tracking and documentation commonly is a failing identified in compliance audits, and is difficult to manage through action lists, spreadsheets, or other tools that are comfortably manipulated by plant personnel. This paper discusses the recent implementation of a database management system at a chemical plant and chronicles the improvements accomplished through the introduction of a customized system. The system as implemented modeled the normal plant workflows, and provided simple, recognizable user interfaces for ease of use.