Mechanical properties of powders for compaction and tableting: an overview

With the ever-increasing need for development speed, the ability to complete a thorough characterization of formulations with small quantities of material is critical but is possible. Thorough characterization of formulation components (both the API and excipients) is a valuable precursor to initiating tablet formulation development activities. Physicochemical and mechanical property data provides key information and insight needed to select ingredients and unit processes. It also provides a valuable benchmark that allows the formulator to monitor changes and set meaningful specifications in raw materials throughout the development process (i.e., QbD). The appropriate use of small scale equipment and, most importantly, the careful and thorough physicochemical and mechanical property characterization at every step of the manufacturing process facilitates the development of robust and well--characterized formulations that can be more easily scaled. Compaction is the critical unit process that is the focus of this discussion. Meaningful tablet compaction using small quantities of formulation is possible with tablet compaction simulators, emulators, and even with a simple hydraulic press. The critical information to be obtained is tablet: compactibility, compressibility, tabletability, and manufacturability as a function of tablet solid fraction. Compactibility has been shown to be essentially independent of compaction speed whereas tabletability, compressibility, and manufacturability may be significantly influenced by compaction speed (dwell time) and this is valuable information. This presentation will discuss the generation, interpretation, and application of this vital compaction data to direct compression and dry granulation formulations using tablet press simulation/emulation

In Vivo Predictive Dissolution: Comparing the Effect of Bicarbonate and Phosphate Buffer on the Dissolution of Weak Acids and Weak Bases

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113173/1/jps24460.pd

The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: Mechanistic modeling and application to progesterone

A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility–permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability ( P m ) as well as the unstirred water layer (UWL) permeability ( P aq ), to predict the overall effective permeability ( P eff ) dependence on cyclodextrin concentration ( C CD ). The analysis reveals that: (1) UWL permeability markedly increases with increasing C CD since the effective UWL thickness quickly decreases with increasing C CD ; (2) membrane permeability decreases with increasing C CD , as a result of the decrease in the free fraction of drug; and (3) since P aq increases and P m decreases with increasing C CD , the UWL is effectively eliminated and the overall P eff tends toward membrane control, that is, P eff  ≈  P m above a critical C CD . Application of this transport model enabled excellent quantitative prediction of progesterone P eff as a function of HPΒCD concentrations in PAMPA assay, Caco-2 transepithelial studies, and in situ rat jejunal-perfusion model. This work demonstrates that when using cyclodextrins as pharmaceutical solubilizers, a trade-off exists between solubility increase and permeability decrease that must not be overlooked; the transport model presented here can aid in striking the appropriate solubility–permeability balance in order to achieve optimal overall absorption. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2739–2749, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71376/1/22033_ftp.pd

Understanding Pharmaceutical Quality by Design

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review

Magnetic resonance imaging quantification of fasted state colonic liquid pockets in healthy humans

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or “pockets”. Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment

Formulation predictive dissolution (fPD) testing to advance oral drug product development: an introduction to the US FDA funded ‘21st Century BA/BE’ project

Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions

Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state

Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds

In Viv o Predictive Dissolution: Transport Analysis of the CO 2 , Bicarbonate In Vivo Buffer System

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109280/1/jps24108.pd