Publications by authors named "Jennifer B Dressman"

105 Publications

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Carbamazepine.

J Pharm Sci 2021 Feb 18. Epub 2021 Feb 18.

Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered "highly soluble" across the range of pH values usually encountered in the upper gastrointestinal tract. Furthermore, evidence in the open literature suggests that carbamazepine is a BCS Class 2 drug. Nevertheless, the oral absolute bioavailability of carbamazepine lies between 70 - 78% and both in vivo and in vitro data support the classification of carbamazepine as a highly permeable drug. Since the therapeutic and toxic plasma level ranges overlap, carbamazepine is considered to have a narrow therapeutic index. For these reasons, a BCS based biowaiver for IR tablets of carbamazepine cannot be recommended. Interestingly, in nine out of ten studies, USP dissolution conditions (900 mL water with 1% SLS, paddle, 75 rpm) appropriately discriminated among bioinequivalent products and this may be a way forward to predicting whether a given formulation will be bioequivalent to the comparator product.
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http://dx.doi.org/10.1016/j.xphs.2021.02.019DOI Listing
February 2021

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metformin Hydrochloride.

J Pharm Sci 2021 Jan 13. Epub 2021 Jan 13.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA. Electronic address:

Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin's Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transporter-mediated drug and is highly soluble, but only 50% of an orally administered dose is absorbed from the gut. Therefore, metformin is a BCS Class III substance. A BCS-based approval approach for major changes to marketed products and new generics is admissible if test and reference dosage forms have the identical active pharmaceutical ingredient and if in vitro dissolution from both are very rapid (i.e. at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Recent International Council for Harmonisation BCS guidance indicates all excipients for Class III biowaivers are recommended to be qualitatively the same and quantitatively similar (except for preservatives, flavor agents, colorant, or capsule shell or film coating excipients). However, despite metformin being a prototypical transporter-mediated drug, there is no evidence that commonly used excipients impact metformin absorption, such that this restriction on excipients for BCS III drugs merits regulatory relief. Commonly used excipients in usual amounts are not likely to impact metformin absorption.
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http://dx.doi.org/10.1016/j.xphs.2021.01.011DOI Listing
January 2021

The use of PBPK/PD to establish clinically relevant dissolution specifications for zolpidem immediate release tablets.

Eur J Pharm Sci 2020 Dec 29;155:105534. Epub 2020 Aug 29.

Institute of Pharmaceutical Technology, Goethe University, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Division of Translational Medicine and Pharmacology, Max von Lauer St. 9, Frankfurt am Main, 60438, Germany. Electronic address:

Background: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (T) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another.

Objectives: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant "safe space" for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the "safe space" for dissolution.

Methods: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy.

Results: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the "safe space" based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem.

Conclusions: A PBPK/PD model indicates that current BCS-biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling.
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http://dx.doi.org/10.1016/j.ejps.2020.105534DOI Listing
December 2020

Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies.

Pharmaceutics 2019 Nov 4;11(11). Epub 2019 Nov 4.

Institute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, 4132 Muttenz, Switzerland.

Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.
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http://dx.doi.org/10.3390/pharmaceutics11110577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920921PMC
November 2019

A novel in vivo predictive dissolution testing coupled with a modeling and simulation for hydrogel matrix monolithic extended release oral dosage forms.

Eur J Pharm Sci 2019 Oct 14;138:105044. Epub 2019 Aug 14.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max-von-Laue Straße 9, D-60438 Frankfurt am Main, Germany.

The objective of this research was to design a novel in vitro dissolution testing for hydrogel matrix monolithic extended release tablets, in which physiologically relevant conditions of swelling, stress, and erosion for the tablets in the fasted gastrointestinal tract are taken into consideration. Mirabegron extended release tablets (three variations) were used as model formulations in this research. In in vitro dissolution testing, the tablets were allowed to swell in 10 mL of dissolution medium, after which they were stressed under a pressure of ca. 300 g/cm and then allowed to erode in a very limited volume of intestinal fluid. The drug release results from this in vitro test were coupled with in silico modeling and simulation to predict individual plasma concentration profiles after oral administration of the extended release tablets to beagle dogs. The results of the in silico simulations indicated that the proposed approach is able to predict in vivo performance of the hydrogel matrix monolithic extended release tablets in individualized simulations.
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http://dx.doi.org/10.1016/j.ejps.2019.105044DOI Listing
October 2019

PBPK modeling coupled with biorelevant dissolution to forecast the oral performance of amorphous solid dispersion formulations.

Eur J Pharm Sci 2019 Jul 22;135:83-90. Epub 2019 May 22.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max-von-Laue Straße 9, D-60438 Frankfurt am Main, Germany.

The aim of this research was to develop an in silico modeling and simulation approach to predict the oral performance of a poorly soluble drug candidate, T2CP, formulated as an amorphous solid dispersion and an amorphous powder. The dissolution and precipitation profiles of T2CP of the two amorphous formulations were evaluated in biorelevant media using USP 2 paddle apparatus. Three equations, the Noyes-Whitney equation for dissolution and separate equations describing nucleation and crystal growth, were fitted simultaneously to the in vitro profiles to estimate the dissolution and precipitation parameters for each formulation. The in silico prediction model for the amorphous formulations was designed using STELLA Professional software and the simulated profiles were compared with the observed plasma profiles in dogs. The STELLA model was able to describe the complex characteristics of in vitro dissolution and precipitation of the amorphous formulations well. The predicted plasma concentration profiles using the estimated dissolution and precipitation parameters of the two amorphous formulations were close to the profiles observed in dogs. This research paves the way for further application of biorelevant in vitro methods in combination with in silico tools to mechanistically forecast the in vivo performance of enhanced formulations.
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http://dx.doi.org/10.1016/j.ejps.2019.05.013DOI Listing
July 2019

The Discriminatory Power of the BCS-Based Biowaiver: A Retrospective With Focus on Essential Medicines.

J Pharm Sci 2019 09 3;108(9):2824-2837. Epub 2019 May 3.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

This article summarizes historic developments, recent expert opinions, and (currently) unresolved challenges concerning the Biopharmaceutics Classification System (BCS)-based Biowaiver. An overview of approval statistics and application potential, case examples addressing the discriminatory power of the procedure, as well as an outlook on possible refinements in the future are provided and critically discussed. Over the last decade, regulatory guidance documents have been harmonized, for example, following scientific consent on allowing biowaivers for BCS class III drugs, making over 50% of orally administered drugs on the World Health Organization Essential Medicines List eligible for an abbreviated approval. Biowaiver monographs that present a complete risk-benefit evaluation for individual drugs have been issued by the International Pharmaceutical Federation for more than 25% of those drugs with the long-range aim of covering all essential drugs. Unresolved issues that have emerged from reported examples of false-negative and false-positive outcomes in the literature demand further adjustments to the regulatory requirements. Possible solutions for resolving these issues are the use of modeling and simulation and refined biorelevant in vitro tests that are better able to discriminate between dosage forms with unequal performance in vivo, potentially allowing biowaivers for selected BCS II drugs.
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http://dx.doi.org/10.1016/j.xphs.2019.04.030DOI Listing
September 2019

The PEARRL reviews - innovative drug development strategies tailored to facilitate earlier access to new oral medicines.

J Pharm Pharmacol 2019 Apr;71(4):439-440

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1111/jphp.13083DOI Listing
April 2019

Predicting the Changes in Oral Absorption of Weak Base Drugs Under Elevated Gastric pH Using an In Vitro-In Silico-In Vivo Approach: Case Examples-Dipyridamole, Prasugrel, and Nelfinavir.

J Pharm Sci 2019 Jan 10;108(1):584-591. Epub 2018 Nov 10.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max-von-Laue Straße 9, D-60438 Frankfurt am Main, Germany.

The aim of the current research was to develop an in silico oral absorption model coupled with an in vitro dissolution/precipitation testing to predict gastric pH-dependent drug-drug interactions for weakly basic drugs. The effects of elevated gastric pH on the plasma profiles of dipyridamole, prasugrel, and nelfinavir were simulated and compared with pharmacokinetic data reported in humans with or without use of proton pump inhibitors or histamine H receptor antagonists. The in vitro dissolution and precipitation data for the weakly basic drugs in biorelevant media were obtained using paddle apparatus. An in silico prediction model based on the STELLA software was designed and simulations were conducted to predict the oral pharmacokinetic profiles of the 3 drugs under both usual (low) and elevated gastric pH conditions. The changes in oral absorption of dipyridamole and prasugrel in subjects with elevated gastric pH compared with those with low stomach pH were predicted well using the in vitro-in silico-in vivo approach. The proposed approach could become a powerful tool in the formulation development of poorly soluble weak base drugs.
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http://dx.doi.org/10.1016/j.xphs.2018.11.008DOI Listing
January 2019

Effects of medicines used to treat gastrointestinal diseases on the pharmacokinetics of coadministered drugs: a PEARRL Review.

J Pharm Pharmacol 2019 Apr 30;71(4):643-673. Epub 2018 Jul 30.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.

Objectives: Drugs used to treat gastrointestinal diseases (GI drugs) are widely used either as prescription or over-the-counter (OTC) medications and belong to both the 10 most prescribed and 10 most sold OTC medications worldwide. The objective of this review article is to discuss the most frequent interactions between GI and other drugs, including identification of the mechanisms behind these interactions, where possible.

Key Findings: Current clinical practice shows that in many cases, these drugs are administered concomitantly with other drug products. Due to their metabolic properties and mechanisms of action, the drugs used to treat gastrointestinal diseases can change the pharmacokinetics of some coadministered drugs. In certain cases, these interactions can lead to failure of treatment or to the occurrence of serious adverse events. The mechanism of interaction depends highly on drug properties and differs among therapeutic categories. Understanding these interactions is essential to providing recommendations for optimal drug therapy.

Summary: Interactions with GI drugs are numerous and can be highly significant clinically in some cases. While alterations in bioavailability due to changes in solubility, dissolution rate, GI transit and metabolic interactions can be (for the most part) easily identified, interactions that are mediated through other mechanisms, such as permeability or microbiota, are less well-understood. Future work should focus on characterising these aspects.
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http://dx.doi.org/10.1111/jphp.12983DOI Listing
April 2019

In vitro methods to assess drug precipitation in the fasted small intestine - a PEARRL review.

J Pharm Pharmacol 2019 Apr 28;71(4):536-556. Epub 2018 Jun 28.

Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Zografou, Greece.

Objectives: Drug precipitation in vivo poses a significant challenge for the pharmaceutical industry. During the drug development process, the impact of drug supersaturation or precipitation on the in vivo behaviour of drug products is evaluated with in vitro techniques. This review focuses on the small and full scale in vitro methods to assess drug precipitation in the fasted small intestine.

Key Findings: Many methods have been developed in an attempt to evaluate drug precipitation in the fasted state, with varying degrees of complexity and scale. In early stages of drug development, when drug quantities are typically limited, small-scale tests facilitate an early evaluation of the potential precipitation risk in vivo and allow rapid screening of prototype formulations. At later stages of formulation development, full-scale methods are necessary to predict the behaviour of formulations at clinically relevant doses. Multicompartment models allow the evaluation of drug precipitation after transfer from stomach to the upper small intestine. Optimisation of available biopharmaceutics tools for evaluating precipitation in the fasted small intestine is crucial for accelerating the development of novel breakthrough medicines and reducing the development costs.

Summary: Despite the progress from compendial quality control dissolution methods, further work is required to validate the usefulness of proposed setups and to increase their biorelevance, particularly in simulating the absorption of drug along the intestinal lumen. Coupling results from in vitro testing with physiologically based pharmacokinetic modelling holds significant promise and requires further evaluation.
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http://dx.doi.org/10.1111/jphp.12951DOI Listing
April 2019

Past, Present, and Future of Bioequivalence: Improving Assessment and Extrapolation of Therapeutic Equivalence for Oral Drug Products.

J Pharm Sci 2018 10 20;107(10):2519-2530. Epub 2018 Jun 20.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

The growth in the utilization of systems thinking principles has created a paradigm shift in the regulatory sciences and drug product development. Instead of relying extensively on end product testing and one-size-fits-all regulatory criteria, this new paradigm has focused on building quality into the product by design and fostering the development of product-specific, clinically relevant specifications. In this context, this commentary describes the evolution of bioequivalence regulations up to the current day and discusses the potential of applying a Bayesian-like approach, considering all relevant prior knowledge, to guide regulatory bioequivalence decisions in a patient-centric environment.
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http://dx.doi.org/10.1016/j.xphs.2018.06.013DOI Listing
October 2018

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations - a PEARRL review.

J Pharm Pharmacol 2019 Apr 16;71(4):483-509. Epub 2018 May 16.

Merck KGaA, Darmstadt, Germany.

Objectives: Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial-and-error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection.

Key Findings: Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can be guided by molecular rationale. However, more work is required to see widespread application of such an approach for PI selection.

Summary: Precipitation inhibitors are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.
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http://dx.doi.org/10.1111/jphp.12927DOI Listing
April 2019

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride.

J Pharm Sci 2018 07 20;107(7):1761-1772. Epub 2018 Mar 20.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To elucidate the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimalarial proguanil hydrochloride, effective via the parent compound proguanil and the metabolite cycloguanil, is not considered to be a narrow therapeutic index drug. Proguanil hydrochloride salt was shown to be highly soluble according to the U.S. Food and Drug Administration, World Health Organization, and European Medicines Agency guidelines, but data for permeability are inconclusive. Therefore, proguanil hydrochloride is conservatively classified as a BCS class 3 substance. In view of this information and the assessment of risks associated with a false positive decision, a BCS-based biowaiver approval procedure can be recommended for orally administered solid immediate release products containing proguanil hydrochloride, provided well-known excipients are used in usual amounts and provided the in vitro dissolution of the test and reference products is very rapid (85% or more are dissolved in 15 min at pH 1.2, 4.5, and 6.8) and is performed according to the current requirements for BCS-based biowaivers.
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http://dx.doi.org/10.1016/j.xphs.2018.03.009DOI Listing
July 2018

Solubility Determination of Active Pharmaceutical Ingredients Which Have Been Recently Added to the List of Essential Medicines in the Context of the Biopharmaceutics Classification System-Biowaiver.

J Pharm Sci 2018 06 6;107(6):1478-1488. Epub 2018 Feb 6.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

Since the publication of Lindenberg et al., which classified orally administered active pharmaceutical ingredients (APIs) on the 2004 Essential Medicines List (EML) of the World Health Organization according to the Biopharmaceutics Classification System (BCS), various APIs have been added to the EML. In this work, BCS classifications for 16 of the orally administered APIs which were added to the EML after 2004 were determined. To establish a reliable solubility classification for all these compounds, a miniaturized shake-flask method was introduced. This method enables a fast, economical determination of the BCS solubility class while reliably discriminating between "highly soluble" and "not highly soluble" compounds. Nine of the 16 APIs investigated were classified as "highly soluble" compounds, making them potential candidates for an approval of multisource drug products via the BCS-based biowaiver procedure. The choice of dose definition (which currently varies among the guidances pertaining to BCS-based bioequivalence published by various regulatory authorities) had no effect on the solubility classification of any of the 16 substances evaluated. BCS classification of the compounds was then completed using permeability data obtained from the literature. As several APIs decomposed at one or more pH values, a decision tree for determining their solubility was established.
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http://dx.doi.org/10.1016/j.xphs.2018.01.025DOI Listing
June 2018

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid.

J Pharm Sci 2017 12 24;106(12):3421-3430. Epub 2017 Aug 24.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 μg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid.
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http://dx.doi.org/10.1016/j.xphs.2017.08.007DOI Listing
December 2017

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

J Pharm Pharmacol 2017 Oct 20;69(10):1284-1292. Epub 2017 Jun 20.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.

Objectives: Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed.

Key Findings: Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency.

Conclusions: The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation.
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http://dx.doi.org/10.1111/jphp.12767DOI Listing
October 2017

Forecasting gastrointestinal precipitation and oral pharmacokinetics of dantrolene in dogs using an in vitro precipitation testing coupled with in silico modeling and simulation.

Eur J Pharm Biopharm 2017 Oct 13;119:107-113. Epub 2017 Jun 13.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue Straβe 9, D-60438 Frankfurt am Main, Germany.

The aim of the current research was to determine the precipitation kinetics of dantrolene sodium using canine biorelevant in vitro testing and to model the precipitation kinetics by appropriately coupling the data with an in silico tool adapted for dogs. The precipitation profiles of dantrolene sodium solutions were obtained with the in vitro paddle apparatus at a revolution rate of 50rpm. The in silico prediction tool was designed using STELLA software and the predicted plasma concentration profiles of dantrolene using the in vitro precipitation data were compared with the observed in vivo pharmacokinetics in beagle dogs. The plasma profiles of dantrolene, which served as a model weakly acidic drug which precipitates in the upper gastrointestinal tract, was successfully predicted using the in vitro precipitation testing coupled with the in silico modeling and simulation approach. The approach was subsequently used to forecast the effect of pharmaceutical excipients (HPMC/PG) on the ability of the drug to supersaturate in the gut and the resulting pharmacokinetics. The agreement of the simulated pharmacokinetics with the observed values confirms the ability of canine biorelevant media to predict oral performance of enhanced dosage forms in dogs.
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http://dx.doi.org/10.1016/j.ejpb.2017.06.012DOI Listing
October 2017

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril.

J Pharm Sci 2017 08 21;106(8):1933-1943. Epub 2017 Apr 21.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate-labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient.
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http://dx.doi.org/10.1016/j.xphs.2017.04.019DOI Listing
August 2017

Mechanistic investigation of the negative food effect of modified release zolpidem.

Eur J Pharm Sci 2017 May 10;102:284-298. Epub 2017 Mar 10.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, 60438 Frankfurt am Main, Germany. Electronic address:

Aims: When administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in C and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods.

Methods: Pharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Q model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction.

Results: It was possible to simulate the mean plasma profiles using a "middle-out" approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations.

Conclusions: The present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.
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http://dx.doi.org/10.1016/j.ejps.2017.03.011DOI Listing
May 2017

Assessment of Bioequivalence of Weak Base Formulations Under Various Dosing Conditions Using Physiologically Based Pharmacokinetic Simulations in Virtual Populations. Case Examples: Ketoconazole and Posaconazole.

J Pharm Sci 2017 02 16;106(2):560-569. Epub 2016 Nov 16.

Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. Electronic address:

Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions-coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria. The systems-components of validated absorption and PBPK models for KETO and POSA were modified to simulate the above-mentioned clinical scenarios. Virtual bioequivalence studies were then carried out to investigate whether formulation effects on the plasma profile vary with the dosing conditions. The slow precipitation of KETO upon reaching the upper part of the small intestine renders its absorption more sensitive to the completeness of gastric dissolution and thus to the gastric environment than POSA, which is subject to extensive precipitation in response to a pH shift. The virtual bioequivalence studies showed that hypothetical test and reference formulations containing KETO would be bioequivalent only if the microenvironment in the stomach enables complete gastric dissolution. We conclude that physiologically based pharmacokinetic modeling and simulation has excellent potential to address issues close to bedside such as optimizing dosing conditions. By studying virtual populations adapted to various clinical situations, clinical strategies to reduce therapeutic failures can be identified.
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http://dx.doi.org/10.1016/j.xphs.2016.10.008DOI Listing
February 2017

Bridging the Gap Between In Vitro Dissolution and the Time Course of Ibuprofen-Mediating Pain Relief.

J Pharm Sci 2016 12 14;105(12):3658-3667. Epub 2016 Oct 14.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

In vitro-in vivo extrapolation techniques combined with physiologically based pharmacokinetic models represent a feasible approach to establishing links between critical quality attributes and the time course of drug concentrations in vivo. By further integrating the results with pharmacodynamic (PD) models, scientists can also explore the time course of drug effect. The aim of this study was to assess whether differences in dissolution rates would affect the onset, magnitude, and duration of the time course of ibuprofen-mediating pain relief. An integrated in vitro-in vivo extrapolation-physiologically based pharmacokinetic/PD model was used to simulate pharmacokinetic and PD profiles for ibuprofen free acid (IBU-H) and its salts. Two elements of the pharmacokinetic profile, the peak of exposure (C) and the time to peak concentration (T), were sensitive to dissolution rate, whereas only 1 element of the pharmacodynamic profile was affected, namely the onset of drug action. The C differences between IBU-H and its salts seem to be mitigated in the (hypothetical) effect compartment because of the concurrent distribution and elimination processes. Furthermore, the predicted maximum concentration in the effect compartment exceeded the EC value, which marks the plateau phase of the PD concentration-response curve, regardless of whether IBU-H or its salts were administered. Understanding the target site distribution kinetics and the potential nonlinearities between exposure and response will assist in setting criteria that are more scientifically based for the demonstration of therapeutic equivalence.
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http://dx.doi.org/10.1016/j.xphs.2016.08.024DOI Listing
December 2016

Is it possible to achieve bio-equivalence between an oral solid immediate-release and an analogue enteric-coated formulation?

J Pharm Pharmacol 2016 Oct 27;68(10):1278-89. Epub 2016 Jul 27.

Discovery and Product Development, Global Research and Development, Teva Pharmaceutical Industries, Ltd, Netanya, Israel.

Objectives: While bioequivalence between enteric-coated and immediate-release formulations can be achieved in terms of AUC, gastric emptying of enteric-coated dosage forms is a stochastic event, usually leading to lower Cmax values than those observed with the corresponding immediate release. This article examines challenges of developing enteric-coated dosage forms which are bioequivalent to the corresponding immediate-release formulations in terms of both AUC and Cmax using rasagiline as a model compound.

Methods: In vitro drug release profiles of enteric-coated formulations were obtained and compared to those of the immediate-release formulation by dissolution testing. Pharmacokinetics was evaluated in bioequivalence studies in healthy human volunteers after single oral administration of enteric-coated and immediate-release formulations.

Key Findings: The initial enteric-coated pellet formulation prototype was equivalent in terms of AUC, but differed in Cmax ; a second formulation prototype, consisting of a single-unit core and enteric-coating film, proved to be bioequivalent to immediate-release rasagiline tablets in terms of AUC and Cmax . In vitro, it released rasagiline rapidly at a pH of 6.8.

Conclusions: Despite differences in gastric emptying between disintegrating immediate-release and enteric-coated solid dosage forms, bioequivalence in pharmacokinetic studies was achieved.
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http://dx.doi.org/10.1111/jphp.12597DOI Listing
October 2016

Dissolution Methods to Increasing Discriminatory Power of In Vitro Dissolution Testing for Ibuprofen Free Acid and Its Salts.

J Pharm Sci 2017 01 7;106(1):92-99. Epub 2016 Jul 7.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

The predictive capacity of in vitro dissolution tests using the Biopharmaceutics Classification System (BCS)-based experimental setup to anticipate in vivo bioequivalence outcomes for BCS class 2 weak acids has been questioned. In this work, the effect of buffer concentration media was investigated as a possible approach to ensuring the discriminative capacity of the in vitro dissolution methods. The case example used to test this approach was ibuprofen, formulated as either the free acid or in various salt forms. By matching the concentration of buffers commonly used to prepare media which aim to simulate the intestinal conditions with that of bicarbonate buffer, which is the predominant buffer species in vivo, to arrive at the same surface pH (pH), the discriminative power of the in vitro dissolution tests was improved. To simulate the in vivo results even better, a pretreatment at acidic pH was added to the dissolution test simulating the gastric conditions to create a 2-stage test. With the 2-stage test, it was possible to account for differences in disintegration in a more physiologically relevant way and thus to better reflect the in vivo performance of the various formulations.
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http://dx.doi.org/10.1016/j.xphs.2016.06.001DOI Listing
January 2017

Can dosage form-dependent food effects be predicted using biorelevant dissolution tests? Case example extended release nifedipine.

Eur J Pharm Biopharm 2016 Aug 15;105:193-202. Epub 2016 Jun 15.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max-von-Laue Strasse 9, 60438 Frankfurt am Main, Germany. Electronic address:

Aims: Food intake is known to have various effects on gastrointestinal luminal conditions in terms of transit times, hydrodynamic forces and/or luminal fluid composition and can therefore affect the dissolution behavior of solid oral dosage forms. The aim of this study was to investigate and detect the dosage form-dependent food effect that has been observed for two extended-release formulations of nifedipine using in vitro dissolution tests.

Methods: Two monolithic extended release formulations, the osmotic pump Adalat® XL 60mg and matrix-type Adalat® Eins 30mg formulation, were investigated with biorelevant dissolution methods using the USP apparatus III and IV under both simulated prandial states, and their corresponding quality control dissolution method. In vitro data were compared to published and unpublished in vivo data using deconvolution-based in vitro - in vivo correlation (IVIVC) approaches.

Results: Quality control dissolution methods tended to overestimate the dissolution rate due to the excessive solubilizing capabilities of the sodium dodecyl sulfate (SDS)-containing dissolution media. Using Level II biorelevant media the dosage form dependent food effect for nifedipine was described well when studied with the USP apparatus III, whereas the USP apparatus IV failed to detect the positive food effect for the matrix-type dosage form.

Conclusions: It was demonstrated that biorelevant methods can serve as a useful tool during formulation development as they were able to qualitatively reflect the in vivo data.
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http://dx.doi.org/10.1016/j.ejpb.2016.06.010DOI Listing
August 2016

FaSSIF-V3, but not compendial media, appropriately detects differences in the peak and extent of exposure between reference and test formulations of ibuprofen.

Eur J Pharm Biopharm 2016 Aug 7;105:134-40. Epub 2016 Jun 7.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

Background: The predictive capacity of in vitro dissolution tests using 50mM phosphate buffer at pH 6.8 to anticipate in vivo bioequivalence outcomes for highly permeable and poorly soluble weak acids has been questioned. In previous work, it was shown that using a lower buffer capacity could correctly distinguish the in vivo behavior of products containing ibuprofen free acid and those containing its salts.

Aim: To assess whether adjustments in the composition of the medium, including matching the phosphate buffer concentration to the reported pH0 of dissolving ibuprofen free acid in bicarbonate buffer, as well as in the stirring rate, could detect differences in the extent and peak of exposure between reference and test formulations.

Results: Using the recently revised fasted state simulated intestinal fluid (FaSSIF-V3) with reduced phosphate buffer concentration (5mM), it was possible to predict in vivo differences in peak and extent of exposure between test and reference formulations of ibuprofen.

Conclusion: For ibuprofen products, a modified Biopharmaceutics Classification System (BCS) based biowaiver dissolution test may be a way forward to approve generic products without having to perform pharmacokinetic studies. More studies with other BCS Class 2 weakly acidic compounds would be necessary to assess whether this approach could be applied more generally.
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http://dx.doi.org/10.1016/j.ejpb.2016.06.004DOI Listing
August 2016

Matching phosphate and maleate buffer systems for dissolution of weak acids: Equivalence in terms of buffer capacity of bulk solution or surface pH?

Eur J Pharm Biopharm 2016 Jun 23;103:104-108. Epub 2016 Mar 23.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

The development of in vitro dissolution tests able to anticipate the in vivo fate of drug products has challenged pharmaceutical scientists over time, especially in the case of ionizable compounds. In the seminal model proposed by Mooney et al. thirty-five years ago, the pH at the solid-liquid interface (pH0) was identified as a key parameter in predicting dissolution rate. In the current work it is demonstrated that the in vitro dissolution of the weak acid ibuprofen in maleate and phosphate buffer systems is a function of the pH0, which in turn is affected by properties of the drug and the medium. The reported pH0 for ibuprofen dissolution in bicarbonate buffer, the predominant buffer species in the human small intestine under fasting conditions, can be achieved by reducing the phosphate buffer concentration to 5.0mM or the maleate buffer concentration to 2.2mM. Using this approach to identify the appropriate buffer/buffer capacity combination for in vitro experiments in FaSSIF-type media, it would be possible to increase the physiological relevance of this important biopharmaceutics tool. However, the necessity of monitoring and adjusting the bulk pH during the experiments carried out in 5.0mM phosphate or 2.2mM maleate buffers must also be taken into consideration.
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http://dx.doi.org/10.1016/j.ejpb.2016.03.024DOI Listing
June 2016

Prediction of the precipitation profiles of weak base drugs in the small intestine using a simplified transfer ("dumping") model coupled with in silico modeling and simulation approach.

Eur J Pharm Biopharm 2016 Jun 21;103:95-103. Epub 2016 Mar 21.

Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, D-60438 Frankfurt am Main, Germany.

Background: Precipitation of poorly soluble, weakly basic drugs upon entering the small intestine may lead to poor bioavailability. It would be useful to be able to predict the extent of in vivo precipitation so that formulation measures to counteract this problem can be taken.

Aim: The aim of this research was to characterize the precipitation kinetics of two representative weak base drugs, dipyridamole and ketoconazole in vitro using a simplified transfer model approach, and to establish a predictive model for the total and dissolved concentrations in the small intestine after oral administration using in silico modeling and simulation.

Methods: A simplified transfer ("dumping") method based on the USP paddle apparatus was used to obtain the precipitation profiles of the two weak base drugs by adding a solution of the drug in 0.02N hydrochloric acid to FaSSIF-V2. The observed precipitation curves obtained with various initial concentrations were fitted to first order kinetics. An in silico pharmacokinetic model for weak base drugs with precipitation in the small intestine was designed using STELLA® software and coupled with the precipitation profiles in order to simulate the total and dissolved drug concentrations in the small intestinal lumen in the fasted state in humans.

Results: The predicted total and dissolved concentration curves in small intestine for the two weak base drugs were similar to the concentration profiles observed in vivo. The fraction precipitated of the drugs in the small intestine was also well predicted, although the precipitation of ketoconazole at higher initial concentrations was somewhat overestimated. A sensitivity analysis conducted on the simulation of the precipitation of the drugs indicated that a higher fraction precipitated when gastric emptying was faster and/or the concentration of the drug in the added solution was higher.

Conclusion: The dumping method provides a useful screen for precipitation in the small intestine, especially in the context of early development.
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http://dx.doi.org/10.1016/j.ejpb.2016.03.020DOI Listing
June 2016

Exploratory Investigation of the Limiting Steps of Oral Absorption of Fluconazole and Ketoconazole in Children Using an In Silico Pediatric Absorption Model.

J Pharm Sci 2016 09 15;105(9):2794-2803. Epub 2016 Mar 15.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

Due to the higher total clearance of certain drugs in children than in adults, it is recommended that, in such cases, higher relative doses on a milligram/kilogram basis should be administered to children in order to achieve similar systemic exposure to adults. This is the case for fluconazole and ketoconazole. Even though the lower absorptive surface area and smaller volumes of intestinal fluids in children does not affect fluconazole absorption, cumulative fraction absorbed of ketoconazole seems to be dose dependent. A dose of 200 mg of ketoconazole, which belongs to the class 2a of the Developability Classification System (DCS) in adults, seems to be higher than the maximum absorbable dose in children, and ketoconazole absorption is expected to be solubility limited (i.e., DCS class 2b) in this population, indicating a DCS class migration. Therefore, extrapolating DCS and DCS drug classification from adults to pediatric groups does not seem to be straightforward and the development of specific pediatric classification systems should be a high priority.
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http://dx.doi.org/10.1016/j.xphs.2016.01.027DOI Listing
September 2016

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin.

J Pharm Sci 2016 Apr 5;105(4):1362-9. Epub 2016 Mar 5.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address:

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects.
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http://dx.doi.org/10.1016/j.xphs.2016.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126353PMC
April 2016