Enhancing tablet disintegration characteristics of a highly water-soluble high-drug-loading formulation by granulation process.

The objective of this study was to improve the disintegration and dissolution characteristics of a highly water-soluble tablet matrix by altering the manufacturing process. A high disintegration time along with high dependence of the disintegration time on tablet hardness was observed for a high drug loading (70% w/w) API when formulated using a high-shear wet granulation (HSWG) process. Keeping the formulation composition mostly constant, a fluid-bed granulation (FBG) process was explored as an alternate granulation method using a 2(4-1) fractional factorial design with two center points. FBG batches (10 batches) were manufactured using varying disingtegrant amount, spray rate, inlet temperature (T) and atomization air pressure. The resultant final blend particle size was affected significantly by spray rate (p = .0009), inlet T (p = .0062), atomization air pressure (p = .0134) and the interaction effect between inlet T*spray rate (p = .0241). The compactibility of the final blend was affected significantly by disintegrant amount (p < .0001), atomization air pressure (p = .0013) and spray rate (p = .05). It was observed that the fluid-bed batches gave significantly lower disintegration times than the HSWG batches, and mercury intrusion porosimetry data revealed that this was caused by the higher internal pore structure of tablets manufactured using the FBG batches.

Axial strength test for round flat faced versus capsule shaped bilayer tablets.

There has been increasing interest in fixed dose combination (FDC) therapy. Multi-layer tablets are a popular choice among various technologies to deliver FDCs. In most cases, round flat faced tooling is used in testing tablets as they have the simplest geometry. However, shaped tooling is more common for commercial products and may have an effect on bilayer tablet strength. Capsule shaped bilayer tablets, similar to a commercial image, and holders conforming to the tablet topology, were compared with similar round flat faced bilayer tablets and their corresponding holders. Bilayer tablets were subjected to an axial test device, until fracture and the quantitative breaking force value was recorded. As the second layer compression force increases, regardless of holder design, an increase in breaking force occurs as expected. This consistent trend provides insight regarding the breaking force of capsule shaped bilayer tablets. The results of this study show that at lower second layer compression forces, tablet geometry does not significantly impact the results. However, at higher compression forces, a significant difference in breaking force between tablet geometries exists. Therefore, using a test geometry close to the final commercial tablet image is recommended to have the most accurate prediction for tablet breakage.

Formation of reactive impurities in aqueous and neat polyethylene glycol 400 and effects of antioxidants and oxidation inducers.

A 2,4-dinitrophenylhydrazine (DNPH) precolumn derivatization high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method was developed to quantify levels of formaldehyde and acetaldehyde in polyethylene glycol (PEG) solutions. Formic acid and acetic acid were quantified by HPLC-UV. Samples of neat and aqueous PEG 400 solutions were monitored at 40°C and 50°C to determine effects of excipient source, water content, pH, and trace levels of hydrogen peroxide or iron metal on the formation of reactive impurities. The effects of antioxidants were also evaluated. Formic acid was the major degradation product in nearly all cases. The presence of water increased the rate of formation of all impurities, especially formic acid as did the presence of hydrogen peroxide and trace metals. Acidic pH increased the formation of acetaldehyde and acetic acid. A distribution of unidentified degradation products formed in neat PEG 400 disappeared upon addition of HCl with corresponding increase of formic acid, indicating they were likely to be PEG-formyl esters. Other unidentified degradation products reacted with DNPH to form a distribution of derivatized products likely to be PEG aldehydes. Antioxidants butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate d-alpha tocopheryl polyethylene glycol-1000 succinate, and sodium metabisulfite were effective in limiting reactive impurity formation, whereas ascorbic acid and acetic acid were not.

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.

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.

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.