Towards Virtual Bioequivalence Studies for Oral Dosage Forms Containing Poorly Water-Soluble Drugs: A Physiologically Based Biopharmaceutics Modeling (PBBM) Approach.

The objective of the present study was to develop a physiologically based biopharmaceutics (PBBM) approach to predict the bioequivalence of dosage forms containing poorly soluble drugs. Aripiprazole and enzalutamide were used as model drugs. Variations in the gastrointestinal (GI) physiological parameters of fasted humans were taken into consideration in in vitro biorelevant dissolution testing and in an in silico PBBM simulations. To estimate bioequivalence between dosage forms, the inter-individual variabilities in their performance in virtual human subjects were predicted from the in vitro studies and variability in e.g. gastric emptying and fluid volume in the stomach was also taken into account. Formulations with different in vitro dissolution performance, a solution and a tablet formulation, were used in order to evaluate the accuracy of bioequivalence prediction using the PBBM approach. The bioequivalence parameters, i.e. geometric mean ratio and 90% confidence interval, for both drugs were predicted well in the virtual studies. In order to achieve even more precise predictions, it will be important to continue characterizing GI physiological parameters, along with their variabilities, on both an inter-subject and inter-occasion basis.

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

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.

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

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 and 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.

Biorelevant media to simulate fluids in the ascending colon of humans and their usefulness in predicting intracolonic drug solubility.

PURPOSE: To develop media simulating human colonic fluids (HCFs), to evaluate their use in predicting intracolonic solubility of ketoconazole, danazol and felodipine and to compare solubilities in HCFs with previously determined solubilities in gastric (HGFs) and small intestinal (HIFs) fluids. METHODS: Fasted state simulated colonic fluid (FaSSCoF) and fed state simulated colonic fluid (FeSSCoF) were designed to reflect fluids previously collected from the ascending colon in healthy adults. Solubilities of the three model compounds were determined in HCFs, simulated HCFs, and plain buffers. RESULTS: For ketoconazole, solubilities in FaSSCoF and FeSSCoF were closer than those in the corresponding plain buffers to the solubility in HCFs. For danazol and felodipine, solubilities in FaSSCoF and FeSSCoF predicted solubilities in HCFs. In the fasted state, solubilities of danazol and felodipine in HCFs were higher than or similar to in HGFs or HIFs, while the ketoconazole solubility was lower. In the fed state, solubilities of all three model compounds in HCFs were lower than in HGFs or HIFs. CONCLUSIONS: FaSSCoF and FeSSCoF more closely predict solubility of poorly soluble compounds in HCFs than plain buffers. In most cases, solubility in HCFs differs from those in HGFs and HIFs.

Characterization of the ascending colon fluids in ulcerative colitis.

PURPOSE: To characterize the fluid composition in ascending colon of fasted adults with ulcerative colitis in relapse and in remission with a view to predicting variations on dosage form performance in the lower inflamed gut. METHODS: Twelve patients participated in a two-phase, crossover study. Enrollment to the relapse phase (Phase A) and designation of the remission state for the second colonoscopy (Phase B) were based on Clinical Rachmilewicz Index values. Samples were analyzed for pH and buffer capacity immediately upon collection. After ultracentrifugation, osmolality, surface tension, soluble protein, soluble carbohydrates, and the levels of ten bile acids, seven short-chain fatty acids (SCFAs), three long-chain fatty acids, triglycerides, diglycerides, monoglycerides, phosphatidylcholine, and cholesterol were measured. RESULTS: Total SCFAs are significantly decreased in relapse, but pH remains unaffected. Regardless of remission/relapse status, pH and isobutyric acid levels are lower than in healthy adults. Buffer capacity, osmolality, and soluble protein are higher than in healthy adults. Treatment with prednisolone increases the volume of intracolonic contents. CONCLUSION: Variations in fluid composition of the ascending colon with activity and severity of ulcerative colitis may have an impact on the performance of orally administered products that are targeted to release the therapeutic agent in the colon.

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

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 (Tmax) 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.

Cytochrome P450-mediated metabolism in the human gut wall.

OBJECTIVE: Although the human small intestine serves primarily as an absorptive organ for nutrients and water, it also has the ability to metabolise drugs. Interest in the small intestine as a drug-metabolising organ has been increasing since the realisation that it is probably the most important extrahepatic site of drug biotransformation. KEY FINDINGS: Among the metabolising enzymes present in the small intestinal mucosa, the cytochromes P450 (CYPs) are of particular importance, being responsible for the majority of phase I drug metabolism reactions. Many drug interactions involving induction or inhibition of CYP enzymes, in particular CYP3A, have been proposed to occur substantially at the level of the intestine rather than exclusively within the liver, as originally thought. CYP3A and CYP2C represent the major intestinal CYPs, accounting for approximately 80% and 18%, respectively, of total immunoquantified CYPs. CYP2J2 is also consistently expressed in the human gut wall. In the case of CYP1A1, large interindividual variation in the expression levels has been reported. Data for the intestinal expression of the polymorphic CYP2D6 are conflicting. Several other CYPs, including the common hepatic isoform CYP2E1, are expressed in the human small intestine to only a very low extent, if at all. The distribution of most CYP enzymes is not uniform along the human gastrointestinal tract, being generally higher in the proximal regions of the small intestine. SUMMARY: This article reviews the current state of knowledge of CYP enzyme expression in human small intestine, the role of the gut wall in CYP-mediated metabolism, and how this metabolism limits the bioavailability of orally administered drugs. Possible interactions between drugs and CYP activity in the small intestine are also discussed.

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products.

OBJECTIVES: The dissolution characteristics of immediate-release doxycycline hyclate products with certified in-vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver-based approval. METHODS: Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin-ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy-Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). KEY FINDINGS: The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in-vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over-discriminating. CONCLUSIONS: Bioequivalence of immediate-release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.

Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption.

OBJECTIVES: Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. METHODS: Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. KEY FINDINGS: The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration-time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure. CONCLUSIONS: The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.

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.

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.

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 H2 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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Towards quantitative prediction of oral drug absorption.

Although several routes of administration can be considered for new drug entities, the oral route remains the most popular. To predict the in vivo performance of a drug after oral administration from in vitro data, it is essential that the factors limiting absorption can be modelled. Factors limiting oral drug absorption are typically slow and/or incomplete dissolution, formation of insoluble complexes and/or decomposition in the gastrointestinal lumen, poor net permeability and first-pass metabolism. Although many attempts have been made to make global forecasts of oral bioavailability based on a single parameter (ranging from the partition coefficient [logP] to the polar surface area), it is clear from the diversity of properties that can influence delivery of drugs via the oral route that such an approach can at best lead to a qualitative estimation. To predict in vivo performance in a more quantitative way, it is instead necessary to identify the extent to which each of the aforementioned factors can limit absorption, and then combine the information into a comprehensive model of the absorptive processes. Much progress has been made in the last 10 years on developing methods to pin down the extent to which each of the factors actually limits the absorption of a given compound and, concomitantly, physiological models have been evolved, which show promise in terms of being able to integrate the information generated about each of the individual limiting factors. This article attempts to summarize recent progress on the various fronts as a kind of 'progress report' towards quantitative prediction of oral drug absorption.

Dissolution improvement of four poorly water soluble drugs by cogrinding with commonly used excipients.

The rate of the dissolution of four poorly soluble drugs (EMD 57033, albendazole, danazol and felodipine) was improved by cogrinding them with various excipients (lactose monohydrate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and sodium lauryl sulphate) using a jet-milling technique. Solid state characterization studies by X-ray diffraction and differential scanning calorimetry verified the maintenance of the crystalline state of the active substances after milling. In vitro dissolution of the coground mixtures in biorelevant media was much faster than from micronised drug in the corresponding physical mixtures for all four compounds. Supersaturated solutions were generated in some cases (EMD 50733 and felodipine), but this phenomenon appeared to be drug- and excipient-specific. Cogrinding with lactose monohydrate resulted in fast dissolution with unstable supersaturation for EMD 57033. Cogrinding the same drug with PVP or HPMC produced a more sustained supersaturation. SLS accelerated the dissolution of EMD 50733 but inhibited supersaturation. The results suggest that the cogrinding with selected excipients is a powerful tool to accelerate the dissolution of poorly soluble drugs without converting the drug to the amorphous form or changing the particle size.

Dissolution enhancement of fenofibrate by micronization, cogrinding and spray-drying: comparison with commercial preparations.

Several techniques were compared for improving the dissolution of fenofibrate, a poorly soluble drug. Particle size reduction was realized by jet milling (micronization; cogrinding with lactose, polyvinylpyrrolidone or sodium lauryl sulphate) and by media milling using a bead mill (nanosizing) with subsequent spray-drying. Solid state characterization by X-ray diffraction and Differential Scanning Calorimetry verified the maintenance of the crystalline state of the drug after dry milling and its conversion to the amorphous state during spray-drying. Micronization of fenofibrate enhanced its dissolution rate in biorelevant media (8.2% in 30min) compared to crude material (1.3% in 30min). Coground mixtures of the drug increased the dissolution rate further (up to 20% in 30min). Supersaturated solutions were generated by nanosizing combined with spray-drying, this process converted fenofibrate to the amorphous state. Fenofibrate drug products commercially available on the German and French markets dissolved similarly to crude or micronized fenofibrate, but significantly slower than the coground or spray-dried fenofibrate mixtures. The results suggest that cogrinding and spray-drying are powerful techniques for the preparation of rapidly dissolving formulations of fenofibrate, and could potentially lead to improvements in the bioavailability of oral fenofibrate products.