Predictive Dissolution Testing Research Articles

Level A IVIVC for immediate release tablets confirms in vivo predictive dissolution testing for ibuprofen

A bioequivalence study comparing two fixed dose combination tablets containing 200 mg ibuprofen and 30 mg pseudoephedrine hydrochloride showed bioequivalence for pseudoephedrine AUC and Cmax, but the reference product showed higher Cmax than the test product in fasted conditions. The main difference between products was the presence of tribasic calcium phosphate in the reference tablet, resulting in an increased surface pH of the dissolving ibuprofen particles under gastric and intestinal conditions and, consequently, higher solubility of ibuprofen. A mechanistic model based on mass balance and ionization equilibria was used to calculate the pH of the particle surface under different buffer conditions. The discrepancies in surface pH between test and reference tablet were pronounced in 0.1 M and 0.01 M hydrochloric acid and in diluted maleate 7 mM pH 6.5 and phosphate 5 mM pH 6.7 buffers (but negligible in compendial phosphate buffer pH 6.8. Only those dissolution tests using pre-treatment in acidic conditions could be used to build a one-step in vitro-in vivo correlation (IVIVC). This work shows the potential of these discriminatory and in vivo predictive dissolution methods to obtain IVIVCs for BCS class IIa drugs and for extending BCS biowaivers to BCS class IIa drugs.

Two-step in vitro-in vivo correlations: Deconvolution and convolution methods, which one gives the best predictability? Comparison with one-step approach

Finding predictive dissolution tests and valid IVIVCs are essential activities in generic industry, as they can be used as substitutes of human bioequivalence studies. IVIVCs can be developed by two different strategies: a one-step approach or a two-step approach.The objectives of this work were to compare different deconvolution and convolution methods used in the development of two-step level A IVIVCs and to study if the relationship between the in vitro dissolution rate and the in vivo dissolution rate should guide the decision between using a two-step approach or a one-step approach during the development of a new IVIVC.When the in vitro and the in vivo dissolution rates had a linear relationship, valid and biopredictive two-step IVIVCs were obtained, although there was not a combination of deconvolution and convolution methods that could be named as the best one, as long as all the prediction errors for any combination were within the limits.It was not possible to obtain a valid two-step IVIVC when the relationship between dissolution rates was non-linear, but the one-step approach was able to overcome this fact and it gave valid IVIVCs regardless of whether the relationship between dissolution rates was linear or non-linear.

In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.

Nifedipine Release From Extended-Release Solid Oral Formulations Using In Vitro Dissolution Testing Under Simulated Gastrointestinal Compression

Drug release plays a critical role in defining bioavailability for an extended release solid oral drug products and predictive dissolution tests are desired to establish clinically relevant quality standards for batch release. The objective of this study focuses on exploring the possible impacts of 1 gastrointestinal (GI) parameter for 1 drug: simulated GI contractions on nifedipine release (in 2 extended release solid oral formulations). The 60 mg nifedipine osmotic pump product A, and polymer matrix-based products B and C were examined in the study. An in-house dissolution system was used to simulate various levels of GI contractions on tested samples, and to monitor changes of sample mechanical properties during dissolution testing. The results show that the polymer matrix-based formulation failed to provide controlled release when simulated GI contraction was above 100 g of force. The method may be useful for polymer matrix-based products to assess potential formulation-related interactions with the GI tract during in vivo drug dissolution.

Integrated biopharmaceutical approach in pharmaceutical development and drug characterization: General concept and application

The importance of biopharmaceutical considerations in pharmaceutical development and drug characterization has been well recognized both by pharmaceutical industry and regulatory authorities as a tool to establish predictive relationships between drug product quality attributes (in vitro data) and its clinical performance (in vivo data). In the present paper, contemporary biopharmaceutics toolkit including in vivo predictive dissolution testing, Biopharmaceutics Classification System, physiologically based pharmacokinetic and biopharmaceutics modeling and simulation, in vitro-in vivo correlation and biowaiver, are reviewed with regards to relevant general principles and applicability. The recently introduced innovative strategy for patient-centric drug development using an integrated systems approach grounded in fundamental biopharmaceutics concepts, clinical insights and therapeutic drug delivery targets, described as Biopharmaceutics Risk Assessment Roadmap (BioRAM) is also presented. Further development in the field will benefit from joint efforts and exchange of knowledge and experiences between pharmaceutical industry and regulatory authorities for the common goal to accelerate development of effective and safe drug products designed in accordance with patients? needs and expectations.

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

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/cm2 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.

Advances in In Vivo Predictive Dissolution Testing of Solid Oral Formulations: How Closer to In Vivo Performance?

Dissolution has become an indispensable tool to predict the in vivo performance of dosage form, especially in recent times, because of the increasing complexity of new drugs discovered. Several attempts have been made to modify dissolution, so that it mimics the in vivo behavior to maximum possible accuracy and minimizes the probability of in vivo bioequivalence failures. In this context, several advancements have been reported including drug dissolution/absorption simulating system, bionic system, dissolution/permeation model, biphasic dissolution system, Caco-2 cell monolayer in combination with compendial dissolution apparatus, artificial stomach duodenum model, dynamic gastric model, Netherlands Organization for Applied Scientific Research gastrointestinal model, and many more. The present review highlights the recent advancements in dissolution methods with a focus on in vivo predictive dissolution methods, their advantages and disadvantages, and key factors governing the results obtained. The impact of maintaining sink conditions and use of biorelevant media is also discussed briefly.

PermeaLoop™, a novel in vitro tool for small-scale drug-dissolution/permeation studies

Here we report first experiences with the novel in vitro dissolution/permeation setup PermeaLoop™. It was designed to overcome current limitations of in vivo predictive dissolution testing of enabling formulations, such as lack of relevant absorptive drag to allow for meaningful interplay between dissolution and permeation, as it is occurring in vivo. We propose a novel setup with a high area-to-volume ratio and report as a model case the dissolution/permeation behavior of an enabling formulation of the poorly soluble and poorly permeable drug ABT-869. Mini tablets consisting of an amorphous solid dispersion were tested at a downscaled clinically relevant dose. At room temperature, release was fast, and more than 35% of the employed dose permeated within 6 h. In consequence, the amount in the donor decreased significantly. By contrast, only 9% of the employed dose was released when performing the experiment at 35 °C. Still, most of the released drug permeated into the acceptor (>80%), and the permeation rate was release-dependent and vice versa, i.e. the scenario was highly dynamic. Hence, due to a sufficiently large permeation area the dissolution step became rate-limiting. Therefore, PermeaLoop™ is regarded a promising tool for evaluating enabling formulations.

Measuring the Impact of Gastrointestinal Variables on the Systemic Outcome of Two Suspensions of Posaconazole by a PBPK Model.

For the last two decades, the application of physiologically based pharmacokinetic (PBPK) models has grown exponentially in the field of oral absorption and in a regulatory context. Although these models are widely used, their predictive power should be validated and optimized in order to rely on these models and to know exactly what is going on "under the hood". In this study, an automated sensitivity analysis (ASA) was performed for 11 gastrointestinal (GI) variables that are integrated into the PBPK software program Simcyp®. The model of interest was a previously validated workspace that was able to predict the intraluminal and systemic behavior of two different suspensions of posaconazole in the Simcyp® Simulator. The sensitivity of the following GI parameters was evaluated in this model: gastric and duodenal pH, gastric and duodenal bicarbonate concentrations (reflecting buffer capacity), duodenal bile salts concentration, gastric emptying, the interdigestive migrating motor complex (IMMC), small intestinal transit time (SITT), gastric and jejunal volumes, and permeability. The most sensitive parameters were gastric/duodenal pH and gastric emptying, for both suspensions. The outcome of the sensitivity analyses highlights the important GI variables that must be integrated into an in vivo predictive dissolution test to help and create a rational and scientific framework/design for product development of novel and generic drug products.

Assessing the influence of media composition and ionic strength on drug release from commercial immediate-release and enteric-coated aspirin tablets

The objective of this test series was to elucidate the importance of selecting the right media composition for a biopredictive in-vitro dissolution screening of enteric-coated dosage forms. Drug release from immediate-release (IR) and enteric-coated (EC) aspirin formulations was assessed in phosphate-based and bicarbonate-based media with different pH, electrolyte composition and ionic strength. Drug release from aspirin IR tablets was unaffected by media composition. In contrast, drug release from EC aspirin formulations was affected by buffer species and ionic strength. In all media, drug release increased with increasing ionic strength, but in bicarbonate-based buffers was delayed when compared with that in phosphate-based buffers. Interestingly, the cation species in the dissolution medium had also a clear impact on drug release. Drug release profiles obtained in Blank CarbSIF, a new medium simulating pH and average ionic composition of small intestinal fluid, were different from those obtained in all other buffer compositions studied. Results from this study in which the impact of various media parameters on drug release of EC aspirin formulations was systematically screened clearly show that when developing predictive dissolution tests, it is important to simulate the ionic composition of intraluminal fluids as closely as possible.

Resorption of calcium phosphate materials: Considerations on the in vitro evaluation

Literature is quite abundant concerning the resorption of calcium phosphates. However, articles on in vitro acellular dissolution tests are scarcer, although these immersion experiments are often considered a first step in establishing a predictive dissolution test and understanding the resorption mechanisms. Also, the comparison of results obtained after immersion in model fluids reveals large discrepancies.The first part of this paper is a literature review focused on in vitro aging of apatite, dicalcium phosphate dihydrate (DCPD) and beta tricalcium phosphate (β-TCP). In the second part, experimental findings obtained by immersing DCPD and β-TCP samples in TRIS and PBS solutions for different times demonstrate the influence of the immersion conditions and possible artefacts induced by the experimental protocols. Suggestions are provided to improve the design of in vitro experiments. In addition, the interest to follow-up at the same time and at a local scale physico-chemical, microstructural and mechanical properties is discussed.

In Vivo Predictive Dissolution (IPD) and Biopharmaceutical Modeling and Simulation: Future Use of Modern Approaches and Methodologies in a Regulatory Context.

The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the interindividual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.

Impact of vibration and agitation speed on dissolution of USP prednisone tablets RS and various IR tablet formulations.

Dissolution testing is an in vitro procedure which is widely used in quality control (QC) of solid oral dosage forms and, given that real biorelevant test conditions are applied, can also be used as a predictive tool for the in vivo performance of such formulations. However, if a dissolution method is intended to be used for such purposes, it has to deliver results that are only determined by the quality of the test product, but not by other variables. In the recent past, more and more questions were arising on how to address the effects of vibration on dissolution test results. The present study was performed to screen for the correlation of prednisone dissolution of USP Prednisone Tablets RS with vibration caused by a commercially available vibration source as well as to investigate how drug release from a range of immediate release formulations containing class 1-4 drugs of the biopharmaceutical classification scheme is affected by vibration when performing dissolution experiments at different agitation rates. Results of the present study show that the dissolution process of oral drug formulations can be affected by vibration. However, it also becomes clear that the degree of which a certain level of vibration impacts dissolution is strongly dependent on several factors such as drug properties, formulation parameters, and the design of the dissolution method. To ensure the establishment of robust and predictive dissolution test methods, the impact of variation should thus be considered in method design and validation.

Meeting Report: In Vivo Predictive Dissolution Conference

This report details discussions held over three days, August 4–6, 2014, in Ann Arbor, MI, on current research on in vivo predictive dissolution (IPD) testing. Participants hailed from academia, industry, and governmental bodies, and focused their attention on the role of IPD in various drug products. Academia was well represented at this conference with speakers mainly from the University of Michigan, but also from Europe and Japan. Their approach for development of IPD is mainly based on solubility characteristics of the drug substance. A great deal of attention was drawn to the composition and mechanical properties of dissolution media. Examples presented by speakers from the pharmaceutical industry showed how the findings from academia are implemented in their method development processes. FDA strongly supports the implementation of new approaches to improve the predictive power of dissolution testing. For decades, the pharmaceutical scientific community has been debating whether to separate or consolidate the dissolution testing methodologies used in different stages, from development to market supply, of a drug product lifecycle. Moreover, regulatory authorities are consistently challenged to accelerate their decisions on ascertaining bioequivalence (BE) of pharmaceutical drug products (within one product or from product to product). The proof of bioavailability (BA) requires human studies. In vivo predictive dissolution (IPD) testing may reduce the number of BA studies required and could help to speed up marketing authorization and the total time-to-market process for industry. More than 100 scientists from the United States, Europe, and Japan gathered for three days in Ann Arbor, Michigan, in early August 2014 to develop a white paper that was to serve as an important contribution to the field of in vivo predictive dissolution. U.S. regulatory authorities stimulated the discussions and were ready to consider novel methodologies in their decision-making process. This report summarizes the scientific presentations given at the conference by experts from pharmacopeias, regulatory authorities, academia, and industry around the globe. This report does not discuss a summary of the white paper, since this document will be published separately (1). USP—WHERE DISSOLUTION METHODOLOGY IS STANDARDIZED Erika Stippler (United States Pharmacopeial Convention, USPC) provided a frequency distribution of the dissolution apparatus stipulated in drug product monographs of the current United States Pharmacopeia (USP). The majority of the dissolution methods approved by regulatory authorities in the United States were developed using the compendial paddle or basket apparatus. USP dissolution methods and specifications are the same as those approved by the FDA, and USP General Chapter Dissolution describes the commonly used apparatus for dissolution testing of oral drug products. In the current USP, there are several chapters that are relevant for dissolution/ drug release testing for various dosage forms. The use of a particular dissolution apparatus depends on the specifics of the drug substance and the dosage form under investigation. A survey of all drug product monographs shows that the most commonly used dissolution apparatus is Apparatus 2, followed by Apparatus 1. Additionally, there are drug product monographs that call for the use of modified compendial apparatus (i.e., alternative basket mesh size, peak vessel, or noncompendial apparatus such as the device termed the reciprocating shaker or tube rotator). For the submission of an abbreviated new drug application (ANDA), the appropriate USP method should be used. If no such method is available, the recently revised USP General Chapter The Dissolution Procedure: Development and Validation may provide guidance for the development and validation of a suitable method (2). GREAT INCREASE OF SCIENTIFIC KNOWHOW AND DEMAND AT FDA FDA Office of Pharmaceutical Science Lawrence Yu defined his understanding of the roles of dissolution testing for new and generic drug products to be twofold: • Quality control tool for the evaluation of batch-to-batch consistency. • Surrogate for in vivo performance. The quality standard is a specification established through the clinical performance of the drug product, thus connecting the standard to safety and efficacy; therefore, the quality standard should not be established based on dx.doi.org/10.14227/DT220215P66 e-mail: ceo-phast@phast.com *Corresponding author.

Development strategies for IVIVC in an industrial environment

Product development is typically challenging. There is a strong desire to understand critical performance factors early in order to optimize formulations for Phase III trials or marketing approval. However, over 90% of drugs entering development in humans do not make it to the market. Thus there is a tremendous risk that resources spent early in development will be wasted as candidates attrite. To overcome this apparent dilemma, a Bayesian approach is suggested. In 'traditional' product development, clinical study designs are typically relatively assumption free and often do not consider learning from earlier investigations. A Bayesian approach is one in which prior information is considered when interpreting the results of the current study. A candidate IVIVC can be developed at the earliest stage of clinical development. Subsequently there are multiple opportunities within a typical development program to assess the performance of the preliminary IVIVC as new formulations are introduced. With each introduction, there is an opportunity to either confirm the adequacy of the IVIVC or to identify the need for development of a more predictive dissolution test and IVIVC.

Meeting Report: AAPS Workshop on “Dissolution Testing, Biowaivers and Bioequivalence” in Zagreb, Croatia

The workshop in Zagreb, Croatia, was held at the PLIVA Research Institute Ltd. Conference Hall on October 3 and 4, 2011, with all presentations given in English. All sessions were followed by Q and A panel discussions. Opening remarks were given by Maja Jaksevac Miksa from the Croatian Pharmaceutical Society, followed by four speakers in the morning session. The first talk, “Dissolution Testing—a Powerful Tool in Drug Development,” was given by Dragica Rausl from Pliva. She set the stage for the workshop by providing the purpose, definitions, and terminology of the dissolution test and giving descriptions and case studies of the four classifications in the Biopharmaceutics Classification System (BCS). Then Vivian Gray from V. A. Gray Consulting gave a presentation titled “General Concepts—Design of Dissolution Method Development, including Quality by Design (QBD).” She discussed principles needed to develop a meaningful dissolution test, one that follows the concepts of QbD. After the break, Marija Bogotaj of the University of Ljubljana, Slovenia, discussed “Non-Compendial Approaches to Dissolution Testing.” She gave examples of noncompendial devices that have been reported and discussed devices that could provide gastric-emptying kinetics. She showed a unique device that simulated peristaltic movement using glass beads in a beaker-like device with media. The session ended with a presentation by Nikoletta Fotaki of the University of Bath, UK, on “Predictive Dissolution Testing and Development of IVIVCs.” Her presentation discussed how predictive dissolution can be useful through all stages of product development, especially early stages, and how accurate in vitro simulation of the GI tract (through media and hydrodynamics) can lead to successful IVIVC–IVIVR. In the afternoon, Vivian Gray spoke about GMPs in the Dissolution Lab, and Terry Way, USP (European office), discussed “The Role of Dissolution Testing: USP Perspective.” The second day began with a talk by Johannes Kramer of PHAST, Homburg, Germany, on “Disintegration Instead of Dissolution: A Case Study.” His talk illustrated how a disintegration test could be used as the regulatory test instead of the dissolution test. He gave a case study that employed the use of Statistical Moment Theory: Mean Time to justify the regulatory disintegration test with regulatory authorities. Then Selvira Zulfikari, from HALMED, Croatia, spoke on the Croatian Regulatory Perspective. Evangelos Kotzagiorgis from the EMA discussed the European Regulatory Perspective on dissolution testing. In the afternoon, Johannes Kramer returned with a talk on “Examination of Level B Correlations with a BCS Class 2 Immediate-Release Formulation.” He presented a case study using multisource propafenon film-coated tablets where the use of level B correlation of mean times provided an IVIVC. Nikoletta Fotaki discussed “From Dissolution to BA/BE Studies.” She gave case studies where modeling and appropriate in vivo data led to successful development of IVIVCs. The workshop ended with Senka Radosevic from Pliva speaking on “Importance of Study Design and Metrics for the Proof of Bioequivalence.” She discussed how advancements in methods for IVIVC and predictions can provide essential tools to accelerate development of generic drugs. In the case when in vitro behavior is not a key to in vivo response, it is possible to compensate by planning the most suitable study design and metrics to be utilized for the demonstration of equivalence. Vivian Gray closed the workshop with remarks of thanks to the Croatian organizers and speakers and appreciation for the fine hospitality shown to the Focus Group speakers. She also thanked Maja Jaksevac Miksa for the tour of the Croatian Pharmaceutical Society building. There were about 80 attendees from five countries: Croatia, Serbia, Slovenia, Montenegro, and Bosnia and Herzegovina.

Dynamic Dissolution: A Step Closer to Predictive Dissolution Testing?

The use of compendial dissolution techniques to characterize the performance of oral drug delivery systems is an established area of pharmaceutical science. However, compendial equipment is recognized as being limited in its ability to replicate the dynamic aspects of in vivo dissolution that are associated with dosage form transit through a rapidly changing and complex gastrointestinal lumenal environment. This review provides an overview of noncompendial dissolution models which have been developed to address the deficiencies of the traditional dissolution bath and provide scientists with a way of assessing product performance under physiologically relevant conditions.

Osteomacs: Osteoclast precursors during inflammatory bone disease but regulators of physiologic bone remodeling

Literature is quite abundant concerning the resorption of calcium phosphates. However, articles on in vitro acellular dissolution tests are scarcer, although these immersion experiments are often considered a first step in establishing a predictive dissolution test and understanding the resorption mechanisms. Also, the comparison of results obtained after immersion in model fluids reveals large discrepancies.The first part of this paper is a literature review focused on in vitro aging of apatite, dicalcium phosphate dihydrate (DCPD) and beta tricalcium phosphate (β-TCP). In the second part, experimental findings obtained by immersing DCPD and β-TCP samples in TRIS and PBS solutions for different times demonstrate the influence of the immersion conditions and possible artefacts induced by the experimental protocols. Suggestions are provided to improve the design of in vitro experiments. In addition, the interest to follow-up at the same time and at a local scale physico-chemical, microstructural and mechanical properties is discussed.

Biorelevant Dissolution: Methodology and Application in Drug Development

INTRODUCTION Dissolution testing can play an important role in several areas for drug products as a quality control tool to monitor batch-to-batch consistency of drug release from a dosage form and as an in vitro surrogate for in vivo performance that can guide formulation development and ascertain the need for bioequivalence tests. The possibility of substituting dissolution tests for clinical studies has been revealed by the development of the Biopharmaceutics Classification System, and dissolution tests that can predict the in vivo performance of drug products (usually called “biorelevant” dissolution tests) could serve this purpose (1, 2). In terms of media and hydrodynamics, biorelevant dissolution testing should provide a baseline for drug and dosage-form performance and should be used to guide formulation development, to identify food effects on the dissolution and bioavailability of orally administered drugs, and to identify solubility limitations and stability issues. The importance of the development of predictive dissolution testing is increased by the fact that the majority of drugs currently in development are poorly soluble drugs and by the challenges for new dosage-form approaches.