The objective of the present study was to design and develop a formulation for orally disintegrating tablets (ODTs) of carbamazepine using quality by design principles. The target product profile (TPP) and quality target product profile (QTPP) of ODTs were identified. Risk assessment was carried out by leveraging prior knowledge and experience to define the criticality of factors based on their impact by Ishikawa fishbone diagram and preliminary hazard analysis tool. Box–Behnken response surface methodology was used to study the effect of critical factors on various attributes of ODTs. The independent factors selected were compression pressure (X₁), concentration of sublimating agent (volatile material) (X₂), disintegrant concentration (X₃) and the responses were tablet crushing strength, tablet porosity, disintegration time, water absorption time, tablet friability and drug dissolution. ANOVA and lack of fit test illustrated that selected independent variables had significant effect on the response variables, and excellent correlation was observed between actual and predicted values. Optimization by desirability function indicated that compression pressure, X₁ (1534 lbs), ammonium bicarbonate concentration, X₂ (7.68%) and Kollidon^® CL-SF concentration, X₃ (6%) were optimum to prepare ODT formulation of carbamazepine of desired attributes complying with QTPP. Thus, in the present study, a high level of assurance was established for ODT product quality and performance.

The downstream processing of hot-melt extruded amorphous solid dispersions (ASDs) into tablets is challenging due to the low tabletability of milled ASDs. Typically, the extrudate strand is sized before milling, as the strand cannot be fed directly into the milling system. At the lab scale, the strand can be sized by hand-cutting before milling. For scaling up, pelletizers or chill roll and flaker systems can be used to break strands. Due to the different techniques used, differences in milling and tablet compaction are to be expected. We present a systematic study of the milling and tableting of an extruded ASD of itraconazole with hypromellose acetate succinate (HPMCAS) as a carrier polymer. The strand was sized using different techniques at the end of the extruder barrel (hand-cutting, pelletizer, or chill roll and flaker) before being milled at varying milling speeds with varying screen sizes. The effects of these variables (sizing technology, milling speed, and screen size) on the critical quality attributes (CQAs) of the milled ASD, such as yield, mean particle size (D50), tablet compaction characteristics, and tablet dissolution, were established using response surface methodology. It was found that the CQAs varied according to sizing technology, with chill roll flakes showing the highest percentage yield, the lowest D50, and the highest tabletability and dissolution rate for itraconazole. Pearson correlation coefficient tests indicated D50 as the most important CQA related to tabletability and dissolution. For certain milling conditions, the milling of hand-cut filaments results in similar particle size distributions (PSDs) to the milling of pellets or chill roll flakes.

As final attributes of dosage form largely depend on the properties of excipients used, understanding the effect of physicochemical properties of excipients is important. In the present study, six grades of L-HPC with varying degrees of particle size and hydroxypropyl content and the influence of the grade on compaction as well as disintegration behavior were studied. All grades of L-HPC were compressed at different compression loads to achieve different tablet porosity. Compressibility and compactibility of L-HPC grades were evaluated using a modified Heckel equation and percolation model. Further effects of particle size and hydroxypropyl content of L-HPC on tablet porosity and disintegration time were evaluated using a 3² full-factorial design. From compaction studies, it was found that compressibility of L-HPC largely depends upon the particle size with lower particle size grade showing lower compressibility. Whereas consolidation/bonding behavior of L-HPC is independent of particle size and % hydroxypropyl content. By factorial design, it was found that particle size and % hydroxypropyl content have a significant effect on the disintegration behavior of L-HPC. It was found that smaller particle sizes and higher hydroxypropyl content of L-HPC show longer disintegration time. Thus, careful consideration of excipients selection should be made to achieve desired quality attribute of the product.

The present study is based on the fundamentals of percolation theory and its application in understanding compression and compaction of powder materials. Four materials, i.e. carbamazepine, microcrystalline cellulose, crospovidone and croscarmellose sodium, with dissimilar deformation and compaction behavior were selected to validate the hypotheses of percolation phenomenon. The values of two percolation thresholds, i.e. bond and site, corresponding to the lower and intermediate compression pressures, were determined using Heckel equation. The compactibility of powder materials was evaluated using classical models as well as the power law equation. The values of percolation thresholds were found to better assess the deformation behavior of powder materials compared to the values of mean yield pressure. The power law equation demonstrated better prediction of compactibility of powder materials compared to the classical models. The value of the critical exponent, q, determined using power law equation by plotting tensile strength vs. normalized relative density of powder compacts was found to be closer to the theoretical value of 2.70. Furthermore, the theoretical knowledge of percolation thresholds of individual powder components in the binary mixture was found to be helpful in improving compaction properties of the poorly compactible material, i.e. carbamazepine. Thus percolation theory can be helpful in predicting compression and compaction behavior of powder materials and serve as a potent tool for the successful design of tablet formulations.