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Nowadays, the ever-increasing costs of research and development in the pharmaceutical industry have created a big demand for predicting the performances of drug candidates. Of those, the desire to establish an in vitro-in vivo correlation (IVIVC) to better predict the oral drug exposure for different drug products is a growing need. Once a robust IVIVC is established, the performance of different drug products can be predicted and selected for testing in clinical trials with greater confidence. This tool will significantly reduce the cost and speed of drug development and provide new therapy to the patient faster. In this study, we explore combining the outputs of Triskelion's Gastro-Intestinal Model (Tiny-TIM) and multi-compartment pharmacokinetic model for a 200 mg ibuprofen product. The Loo-Riegelman method was used to calculate the amount of ibuprofen absorbed and was combined with the Tiny-TIM data to establish the IVIVC. The IVIVC was used to predict the exposures of both fast release and liquid gel formulations in humans. In general, the predicted exposure using Tiny-TIM-based IVIVC has good agreement with the clinical findings., Competing Interests: Conflict of Interest The authors declare no conflict of interest in this work., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Amorphous solid dispersions (ASDs) are commonly used to enhance the oral absorption of drugs with solubility or dissolution rate limitations. Although the ASD formulation is typically constrained by physical stability and in vivo performance considerations, ASD particles can be engineered using the spray-drying process to influence mechanical and flow properties critical to tableting. Using the ASD formulation of 20% w/w felodipine dispersed in polyvinyl pyrrolidone vinyl acetate, spray-drying atomization and drying conditions were tuned to achieve 4 different powders with varying particle properties. The resulting particles ranged in volume moment mean diameter from 4 to 115 μm, bulk density from 0.05 to 0.38 g cm -3 , and morphologies of intact, collapsed, and fractured hollow spheres. Powder flowability by shear cell ranged from poor to easy flowing, whereas mechanical property tests suggested all samples will produce strong tablets at reasonable solid fractions and compression pressures. In addition, Hiestand dynamic tableting indices showed excellent dynamic bonding for 3 powders, and low viscoelasticity with high brittleness for all powders. This work demonstrates the extent spray-dried ASD particle morphologies can be engineered to achieve desired powder flow and mechanical properties to mitigate downstream processing risks and increase process throughput., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

In-vitro dissolution testing of pharmaceutical formulations has been used as a quality control test for many years. At early drug product development, in vivo predictive dissolution testing can be used for guidance in the rational selection of candidate formulations that best fit the desired in vivo dissolution characteristics. At present, the most widely applied dissolution media are phosphate-based buffers and, in some cases, the result of dissolution tests performed in such media have demonstrated reasonable/acceptable IVIVCs. However, the presence of phosphates in human GI luminal fluids is insignificant, which makes the use of such media poorly representative of the in vivo environment. The gastrointestinal lumen has long been shown to be buffered by bicarbonate. Hence, much interest in the development of suitable biorelevant in vitro dissolution media based on bicarbonate buffer systems has evolved. However, there are inherent difficulties associated with these buffers, such as maintaining the pH throughout the dissolution test, as CO 2 tends to leave the system. Various mathematical models have been proposed to analyze bicarbonate buffers and they are discussed in this review. Approaches such as using simpler buffer systems instead of bicarbonate have been proposed as surrogate buffers to produce an equivalent buffer effect on drug dissolution on a case-by-case basis. There are many drawbacks related to simpler buffers systems including their poor in vivo predictability. Considerable discrepancies between phosphate and bicarbonate buffer dissolution results have been reported for certain dosage forms, e.g. enteric coated formulations. The role and need of bicarbonate-based buffers in quality control testing requires scientific analysis. This review also encompasses on the use of bicarbonate-based buffers as a potentially in vivo predictive dissolution medium for enteric coated dosage forms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Enteric coatings have shown in vivo dissolution rates that are poorly predicted by traditional in vitro tests, with the in vivo dissolution being considerably slower than in vitro. To provide a more mechanistic understanding of this, the dependence of the release properties of various enteric-coated (EC) products on bulk pH and bicarbonate molarity was investigated. It was found that, at presumably in vivo-relevant values, the bicarbonate molarity is a more significant determinant of the dissolution profile than the bulk pH. The findings also indicate that this steep relationship between the dissolution of enteric coatings and bicarbonate molarity limits those coatings' performance in vivo. This is attributed to the relatively low bicarbonate molarities in human intestinal fluids. Further, the hydration and dehydrations kinetics of carbonic acid and carbon dioxide are not sufficiently rapid to reach equilibrium in the diffusion layer surrounding a dissolving ionizable solid. This results in the effective pKa of bicarbonate in the diffusion layer being lower than that determined potentiometrically at equilibrium in the bulk surrounding fluid. These results demonstrate the importance of thoroughly investigating the intestinal bicarbonate concentrations and using bicarbonate buffers or properly designed surrogates (if possible) when evaluating enteric drug products during product development and quality control., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.

Magnesium stearate is the salt of a complex mixture of fatty acids, with the majority being stearate and palmitate. It has multiple crystalline forms and, potentially, an amorphous form. Magnesium stearate is used in the pharmaceutical manufacturing industry as a powder lubricant, and typically is added at low levels (∼1%) during the manufacturing process and blended for a relatively short time (∼5 min). Proper levels and mixing times are needed, as too short a mixing time or too small a quantity will result in improper lubrication, and too much can negatively impact dissolution rates. The complex mixture of multiple fatty acids and crystalline forms in magnesium stearate leads to variability between commercial sources, and switching between sources can impact both the amount of lubricant and mixing time needed for proper lubrication. In order to better understand the complex nature of magnesium stearate, a variety of analytical techniques were used to characterize both synthesized and commercial magnesium stearate samples. The results show that correlation among differential scanning calorimetry, thermogravimetric analysis, solid-state NMR spectroscopy, and other techniques provides a unique insight into the forms of magnesium stearate. Finally, the ability to monitor form changes of magnesium stearate in an intact tablet using solid-state NMR spectroscopy is shown., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)