Mitigation of Adverse Clinical Events of a Narrow Target Therapeutic Index Compound through Modified Release Formulation Design: An in Vitro, in Vivo, in Silico, and Clinical Pharmacokinetic Analysis.

BMS-914392 is a tricyclic pyranoquinoline BCS class 2 weak base that demonstrates high solubility in low pH environments. Initial clinical studies indicated that rapid release of high dose BMS-914392 led to transient adverse events associated with peak plasma concentrations. A modified release (MR) formulation strategy was proposed to suppress the peak blood concentration and maintain total exposure to overcome the adverse effects. Three modified release prototype formulations were developed and tested via a USP 3 dissolution method to verify that each formulation can effectively slow the release of BMS-914392. A pharmacokinetic (PK) absorption model was employed to guide the formulation development and selection. Simulations showed good agreement with plasma levels measured after oral dosing in dogs. Identification of key formulation factors to achieve release rates suitable for blunting peak blood levels without diminishing exposure were achieved through combined preclinical data and use of GastroPlus simulations. PK absorption model refinements based on phase 1 data, dog pharmacokinetic results, and in vitro data provided reliable predictions of human absorption profiles and variability in patients. All three prototype formulations demonstrated lower maximum plasma concentrations of BMS-914392 and maintained satisfactory relative bioavailability. Both the PK absorption model and subsequent clinical data indicated that an acidified hydrophilic matrix MR formulation had the greatest potential to reduce the incidence of adverse events and showed the best exposure profile in fasted state healthy subjects with and without famotidine coadministration. The risk based development process achieved successful screening and selection of a suitable modified release formulation to enable clinical efficacy trials.

Correlating bilayer tablet delamination tendencies to micro-environmental thermodynamic conditions during pan coating.

OBJECTIVE: The objective of this study was to determine the impact that the micro-environment, as measured by PyroButton data loggers, experienced by tablets during the pan coating unit operation had on the layer adhesion of bilayer tablets in open storage conditions. MATERIALS AND METHODS: A full factorial design of experiments (DOE) with three center points was conducted to study the impact of final tablet hardness, film coating spray rate and film coating exhaust temperature on the delamination tendencies of bilayer tablets. PyroButton data loggers were placed (fixed) at various locations in a pan coater and were also allowed to freely move with the tablet bed to measure the micro-environmental temperature and humidity conditions of the tablet bed. RESULTS: The variance in the measured micro-environment via PyroButton data loggers accounted for 75% of the variance in the delamination tendencies of bilayer tablets on storage (R(2 )= 0.75). A survival analysis suggested that tablet hardness and coating spray rate significantly impacted the delamination tendencies of the bilayer tablets under open storage conditions. The coating exhaust temperature did not show good correlation with the tablets' propensity to crack indicating that it was not representative of the coating micro-environment. Models created using data obtained from the PyroButton data loggers outperformed models created using primary DOE factors in the prediction of bilayer tablet strength, especially upon equipment or scale transfers. CONCLUSION: The coating micro-environment experienced by tablets during the pan coating unit operation significantly impacts the strength of the bilayer interface of tablets on storage.

Effect of hydroxy propyl cellulose grade and foam quality on foam granulation of a high drug load formulation.

Foam granulation is a relatively newer wet granulation process whereby foamed binder solutions are added to the powders in the mixer to reduce localized over-wetting encountered during the wet granulation. This study is the first to investigate the effect of binder grade and foam quality on foam granulation process and granule properties of a high drug load formulation. Two different HPC grades, HPC LF (two times more viscous) and HPC EXF at an equivalent 7.4%w/w solution concentration, and foam quality of 50%, 90% and binder solution dripped were added to a high drug load (81%w/w) formulation for wet granulation. The granules were evaluated for compactibility and resultant compact strengths. The 50% foam quality of either HPC LF and HPC EXF resulted in lowest impeller power reading and water activity compared to 90% foam quality or dripped HPC solution. Granules prepared with 50% foam quality also exhibited smaller granule size, wider size distribution and higher specific surface area, resulting in higher compactibility. Whilst the granules prepared with different foamed HPC grades were not significantly different in compression behavior, they were higher in compact strengths, suggesting that foam mixing was more efficient in binder distribution compared to binder liquid penetration and distribution.

Evaluation of the performance characteristics of bilayer tablets: Part II. Impact of environmental conditions on the strength of bilayer tablets.

Ambient air humidity and temperature are known to influence the mechanical strength of tablets. The objective of this work is to understand the influence of processing parameters and environmental conditions (humidity and temperature) on the strength of bilayer tablets. As part of this study, bilayer tablets were compressed with different layer ratios, dwell times, layer sequences, material properties (plastic and brittle), first and second layer forces, and lubricant concentrations. Compressed tablets were stored in stability chambers controlled at predetermined conditions (40C/45%RH, 40C/75%RH) for 1, 3, and 5 days. The axial strength of the stored tablets was measured and a statistical model was developed to determine the effects of the aforementioned factors on the strength of bilayer tablets. As part of this endeavor, a full 3 × 2(4) factorial design was executed. Responses of the experiments were analyzed using PROC GLM of SAS (SAS Institute Inc, Cary, North Carolina, USA). A model was fit using all the responses to determine the significant interactions (p < 0.05). Results of this study indicated that storage conditions and storage time have significant impact on the strength of bilayer tablets. For Avicel-lactose and lactose-Avicel tablets, tablet strength decreased with the increasing humidity and storage time. But for lactose-lactose tablets, due to the formation of solid bridges upon storage, an increase in tablet strength was observed. Significant interactions were observed between processing parameters and storage conditions on the strength of bilayer tablets.

Evaluation of the performance characteristics of bilayer tablets: Part I. Impact of material properties and process parameters on the strength of bilayer tablets.

Bilayer tableting technology has gained popularity in recent times, as bilayer tablets offer several advantages over conventional tablets. There is a dearth of knowledge on the impact of material properties and process conditions on the performance of bilayer tablets. This paper takes a statistical approach to develop a model that will determine the effect of the material properties and bilayer compression process parameters on the bonding strength and mode of breakage of bilayer tablets. Experiments were carried out at pilot scale to simulate the commercial manufacturing conditions. As part of this endeavor, a seven-factor half-fraction factorial (2(7-1)) design was executed to study the effect of bilayer tablet compression process factors on the bonding strength of bilayer tablets. Factors studied in this work include: material properties (plastic and brittle), layer ratio, dwell time, layer sequence, first- and second-layer forces, and lubricant concentration. Bilayer tablets manufactured in this study were tested using the axial tester, as it considers both the interfacial and individual layer bonding strengths. Responses of the experiments were analyzed using PROC GLM of SAS (SAS Institute Inc, Cary, North Carolina). A model was fit using all the responses to determine the significant interactions (p < 0.05). The results of this study indicated that nature of materials played a critical role on the strength of bilayer compacts and also on mode of fracture. Bilayer tablets made with brittle materials in both the layers are strongest, and fracture occurred in the first layer indicating that interface is stronger than layers. Significant interactions were observed between the selected factors and these results will provide an insight into the interplay of material properties, process parameters, and lubricant concentration on the bonding strength and mode of breakage of bilayer tablets.

Investigation into stability of poly(vinyl alcohol)-based Opadry® II films.

Poly(vinyl alcohol) (PVA)-based formulations are used for pharmaceutical tablet coating with numerous advantages. Our objective is to study the stability of PVA-based coating films in the presence of acidic additives, alkaline additives, and various common impurities typically found in tablet formulations. Opadry® II 85F was used as the model PVA-based coating formulation. The additives and impurities were incorporated into the polymer suspension prior to film casting. Control and test films were analyzed before and after exposure to 40°C/75% relative humidity. Tests included film disintegration, size-exclusion chromatography, thermal analysis, and microscopy. Under stressed conditions, acidic additives (hydrochloric acid (HCl) and ammonium bisulfate (NH(4)HSO(4))) negatively impacted Opadry® II 85F film disintegration while NaOH, formaldehyde, and peroxide did not. Absence of PVA species from the disintegration media corresponded to an increase in crystallinity of PVA for reacted films containing HCl. Films with NH(4)HSO(4) exhibited slower rate of reactivity and less elevation in melting temperature with no clear change in melting enthalpy. Acidic additives posed greater risk of compromise in disintegration of PVA-based coatings than alkaline or common impurities. The mechanism of acid-induced reactivity due to the presence of acidic salts (HCl vs. NH(4)HSO(4)) may be different.

Understanding the Factors That Control the Quality of Mini-Tablet Compression: Flow, Particle Size, and Tooling Dimension.

Despite the increasing importance of mini-tablet for its advantages as pediatric formulations and in modified-release applications, its popularity is limited due to the lack of formulation and processing knowledge in developing such dosage forms. In this study, common grades of microcrystalline cellulose and roller compacted granules with a range of powder properties were used to evaluate the critical material properties required for the successful manufacturing of 1.7-mm mini-tablets. It was found that blends with small particle size had poor flow properties that did not support consistent die filling and also tended to cause tooling jam and damage. While the granulation process was effective in improving blend flow properties by increasing particle size, it is imperative to avoid very large particles that could also cause inadequate flow by blocking the space within the die. Successful mini-tablet compression could be achieved by removing particles larger than roughly 1/3 of the die diameter or milling the granules using a screen less than 1/3 of the die diameter.

Use of similarity scoring in the development of oral solid dosage forms.

In the oral solid dosage form space, material physical properties have a strong impact on the behaviour of the formulation during processing. The ability to identify materials with similar characteristics (and thus expected to exhibit similar behaviour) within the company's portfolio can help accelerate drug development by enabling early assessment and prediction of potential challenges associated with the powder properties of a new active pharmaceutical ingredient. Such developments will aid the production of robust dosage forms, in an efficient manner. Similarity scoring metrics are widely used in a number of scientific fields. This study proposes a practical implementation of this methodology within pharmaceutical development. The developed similarity metrics is based on the Mahalanobis distance. Scanning electron microscopy was used to confirm morphological similarity between the reference material and the closest matches identified by the metrics proposed. The results show that the metrics proposed are able to successfully identify material with similar physical properties.

Mechanistic insights into the scale-up of the roller compaction process: a practical and dimensionless approach.

Although the roller compaction process appears simple, efforts to quantitatively model the process have proven challenging because of complex material behavior in the feeding and compaction zones. To date, implementation of roller compaction models to experimental work has been limited because these models typically require large experimental data sets or obscure input parameters that are difficult to obtain experimentally. In this work, an alternative approach has been established, expanding upon a widely used roller compaction model, Johanson's model, to enable its incorporation into a daily workflow. The proposed method requires only standard, routinely measured parameters as inputs. An excellent correlation between simulated and experimental results has been achieved for placebo and active blends up to 22% (w/w) drug load. Furthermore, a dimensionless relationship between key process parameters and final compact properties was elucidated. This dimensionless parameter, referred to as the modified Bingham number (Bm *), highlights the importance of balancing yield and viscous stresses during roller compaction to achieve optimal output properties. By maintaining a constant ratio of yield-to-viscous stresses, as indicated by a constant Bm *, consistent products were attained between two scales of operation. Bm * was shown to provide guidance toward determining the design space for formulation development, as well as to facilitate scale-up development.

Influence of compaction properties and interfacial topography on the performance of bilayer tablets.

Bilayer tablets are generating great interest recently as they can achieve controlled delivery of different drugs with pre-defined release profiles. However, the production of such tablets has been facing great challenges as the layered tablets are prone to delaminate or fracture in the individual layers due to insufficient bonding strength of layers and adhesion at the interfaces. This paper will provide an insight into the role of interfacial topography on the performance of the bilayer tablets. In this study, two widely used pharmaceutical excipients: microcrystalline cellulose and lactose were investigated. Bilayer tablets were manufactured with a range of first and second layer compression forces. A crack of known dimensions was introduced at the interface to investigate the crack propagation mechanisms upon axially loading the bilayer tablet, and to determine the stress intensity factor (K(I)) of the interface (will be discussed in a separate paper). The results indicated that a strong dependency of the strength of bilayer tablets and mode of crack propagation on the material and compaction properties. The results showed that the strength of bilayer tablets increased with the increase of interfacial roughness, and the first layer and second layer forces determined the magnitude of interfacial roughness for both plastic and brittle materials. Further, the results also indicated that layer sequence and compaction forces played a key role in influencing the strength of the bilayer tablets. For the same (first and second layer) force combination, interfacial strength is higher for the tablets made of brittle material in the first layer. It was observed that interfacial strength decreased with the increase of lubricant concentration. The studies showed that the effect of lubricant (i.e. reduction in compact strength with the increase of lubricant concentration) on the strength of compacts is higher for tablets made of plastic material as compared to the tablets made of brittle material.