A Chewing Study of Abuse-Deterrent Tablets Containing Polyethylene Oxide Using a Robotic Simulator.

Abuse-deterrent formulations (ADFs) refer to formulation technologies aiming to deter the abuse of prescription drugs by making the dosage forms difficult to manipulate or extract the opioids. Assessments are required to evaluate the performance of the drugs through different routes including injection, ingestion, and insufflation and also when the drugs are manipulated. Chewing is the easiest and most convenient way to manipulate the drugs and deserves investigation. Chewing is one of the most complex bioprocesses, where the ingested materials are subject to periodic tooth crushing, mixed through the tongue, and lubricated and softened by the saliva. Inter- and intra-subject variations in chewing patterns may result in different chewing performances. The purpose of this study is to use a chewing simulator to assess the deterrent properties of tablets made of polyethylene oxide (PEO). The simulator can mimic human molar grinding with variable chewing parameters including molar trajectory, chewing frequency, and saliva flow rate. To investigate the effects of these parameters, the sizes of the chewed tablet particles and the chewing force were measured to evaluate the chewing performance. Thirty-four out of forty tablets were broken into pieces. The results suggested that the simulator can chew the tablets into smaller particles and that the molar trajectory and saliva flow rate had significant effect on reducing the size of the particles by analysis of variance (ANOVA) while the effect of chewing frequency was not clear. Additionally, chewing force can work as an indicator of the chewing performance.

The effect of food vehicles on in vitro performance of pantoprazole sodium delayed release sprinkle formulation.

Certain patient populations, including children, the elderly or people with dysphagia, find swallowing whole medications such as tablets and capsules difficult. To facilitate oral administration of drugs in such patients, a common practice is to sprinkle the drug products (e.g., usually after crushing the tablet or opening the capsule) on food vehicles before consumption which improves swallowability. Thus, evaluation of the impact of food vehicles on the potency and stability of the administered drug product is important. The aim of the current study was to evaluate the physicochemical properties (viscosity, pH, and water content) of common food vehicles used for sprinkle administration (e.g., apple juice, applesauce, pudding, yogurt, and milk) and their impacts on the in vitro performance (i.e., dissolution) of pantoprazole sodium delayed release (DR) drug products. The food vehicles evaluated exhibited marked difference in viscosity, pH and water content. Notably, the pH of the food as well as the interaction between food vehicle pH and drug-food contact time were the most significant factors affecting the in vitro performance of pantoprazole sodium DR granules. For example, the dissolution of pantoprazole sodium DR granules sprinkled on food vehicles of low pH (e.g., apple juice or applesauce) for short durations remained unchanged compared with the control group (i.e., without mixing with food vehicles). However, use of high pH food vehicles (e.g., milk) with prolonged contact time (e.g., 2 h) resulted in accelerated pantoprazole release, drug degradation and loss of potency. Overall, a thorough assessment of physicochemical properties of food vehicles and formulation characteristics are a necessary part of the development of sprinkle formulations.

Exploring the Relationship of Drug BCS Classification, Food Effect, and Gastric pH-Dependent Drug Interactions.

Food effect (FE) and gastric pH-dependent drug-drug interactions (DDIs) are both absorption-related. Here, we evaluated if Biopharmaceutics Classification System (BCS) classes may be correlated with FE or pH-dependent DDIs. Trends in FE data were investigated for 170 drugs with clinical FE studies from the literature and new drugs approved from 2013 to 2019 by US Food and Drug Administration. A subset of 38 drugs was also evaluated to determine whether FE results can inform the need for a gastric pH-dependent DDI study. The results of FE studies were defined as no effect (AUC ratio 0.80-1.25), increased exposure (AUC ratio ≥1.25), or decreased exposure (AUC ratio ≤0.8). Drugs with significantly increased exposure FE (AUC ratio ≥2.0; N=14) were BCS Class 2 or 4, while drugs with significantly decreased exposure FE (AUC ratio ≤0.5; N=2) were BCS Class 1/3 or 3. The lack of FE was aligned with the lack of a pH-dependent DDI for all 7 BCS Class 1 or 3 drugs as expected. For the 13 BCS Class 2 or 4 weak base drugs with an increased exposure FE, 6 had a pH-dependent DDI (AUC ratio ≤0.8). Among the 16 BCS Class 2 or 4 weak base drugs with no FE, 6 had a pH-dependent DDI (AUC ratio ≤0.8). FE appears to have limited correlation with BCS classes except for BCS Class 1 drugs, confirming that multiple physiological mechanisms can impact FE. Lack of FE does not indicate absence of pH-dependent DDI for BCS Class 2 or 4 drugs. Graphical Abstract.

A microcrystalline cellulose based drug-composite formulation strategy for developing low dose drug tablets.

The uniformity of active pharmaceutical ingredient (API) is a main challenge associated with manufacturing low dose tablets. Here, we present a binder enhanced API-microcrystalline cellulose (BEAM) approach to address this challenge. In the BEAM approach a powder is prepared by spraying a PVP hydro-alcoholic solution, which contains API at an appropriate concentration, onto a powder bed of microcrystalline cellulose (MCC) under high shear. BEAM powders of 5 model APIs, with solubility spanning a range of 5 orders of magnitude, all exhibited excellent flowability, tabletability, and low ejection force. Therefore, all BEAM powders could be directly compressed into tablets with excellent API uniformity and fast disintegration without using any other excipients. Compared to traditional ways to address content uniformity problems, this formulation strategy is much more robust and simpler, making it a potential platform technology for manufacturing tablets of potent APIs.

Comparative analyses of flow and compaction properties of diverse mannitol and lactose grades.

Appropriate selection of excipient grade during tablet formulation development depends on thorough knowledge in their compaction and flow properties. Each chemically unique pharmaceutical excipient is usually available in several commercial grades that are widely different in powder properties, which influence their performance for a specific formulation application. In this work, 11 grades of mannitol were systematically characterized, in terms of their particulate, flow and tableting properties, and compared against 5 grades of lactose. Principal component analysis (PCA) identified significant correlations among selected variables, such as particle size, surface area, flowability, wall friction, plasticity parameter, tensile strength, and tablet brittleness. PCA also revealed similar grades of the two excipients, which may be used to select replacement grade, if needed, based on similarity in their overall properties.

A mesoporous silica based platform to enable tablet formulations of low dose drugs by direct compression.

Achieving adequate content uniformity (CU) is a significant challenge in the development and manufacturing of low dose oral tablets. Using four model active pharmaceutical ingredients (APIs), we show that loading APIs into a grade of mesoporous silica, Aeroperl®, is effective for achieving excellent CU. All APIs in the Aeroperl® composites were amorphous. After six months under accelerated stability conditions, the drug-Aeoperl composites exhibited good physical stability for all four APIs. The performance of Aeroperl®-based formulations was robust since their good CU and manufacturability were insensitive to model APIs. In addition, the dissolution rate of composite-based formulations was higher than corresponding physical mixtures. Overall, the Aeroperl®-based platform formulation is a promising approach for successfully developing low dose oral tablet products.

Ribbon thickness influences fine generation during dry granulation.

Uncontrolled fine generation during the milling process is a challenge for dry granulation by roller compaction. Here, we report the observation that ribbon thickness can significantly influence percentage of fines. Thus, among other parameters, ribbon thickness needs to be controlled for the development of a robust roller compaction process and ensure successful scale up.

Particle Engineering for Enabling a Formulation Platform Suitable for Manufacturing Low-Dose Tablets by Direct Compression.

Maintaining good content uniformity (CU) is a significant challenge for low-dose oral tablets in particular when using direct compression (DC). Using 6 model active pharmaceutical ingredients, we show that a platform DC tablet formulation suitable for developing low-dose API with excellent CU can be developed. This platform formulation is enabled by particle engineering, where an API of interest is loaded in a suitable porous carrier to form a uniform API-carrier composite. Powder properties of such composite particles are dictated by the properties of the carrier, which are insensitive to chemical structure and loading level of the API. Powder flowability, tabletability, tablet friability, and tablet disintegration time are all excellent and only vary within a narrow range among the 6 model APIs. Nearly 100% drug can be released in water from tablets composed of the 6 model APIs. Thus, the approach described here holds the promise for broad application in developing low-dose tablet products using DC possessing excellent CU and other critical quality attributes.

Resveratrol cocrystals with enhanced solubility and tabletability.

Two new 1:1 cocrystals of resveratrol (RES) with 4-aminobenzamide (RES-4ABZ) and isoniazid (RES-ISN) were synthesized by liquid assisted grinding (LAG) and rapid solvent removal (RSR) methods using ethanol as solvent. Their physiochemical properties were characterized using PXRD, DSC, solid state and solution NMR, FT-IR, and HPLC. Pharmaceutically relevant properties, including tabletability, solubility, intrinsic dissolution rate, and hygroscopicity, were evaluated. Temperature-composition phase diagram for RES-ISN cocrystal system was constructed from DSC data. Both cocrystals show higher solubility than resveratrol over a broad range of pH. They are phase stable and non-hygroscopic even under high humidity conditions. Importantly, both cocrystals exhibit improved solubility and tabletability compared with RES, which make them more suitable candidates for tablet formulation development.

Dependence of tablet brittleness on tensile strength and porosity.

An analysis of data collected from 25 sets of diverse pharmaceutical powders has identified that an exponential growth function satisfactorily describes the relationship between tablet brittleness and tablet porosity while a power law function well describes the relationship between tablet brittleness and tensile strength. These equations have the potential to facilitate better characterization of tablet mechanical properties and to guide the design and optimization of pharmaceutical tablet products.