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A majority of drugs marketed in amorphous formulations have a good glass-forming ability, while compounds less stable in the amorphous state still pose a formulation challenge. This work explores ternary solid dispersions of two model drugs with a polymer (i.e., hydroxypropyl cellulose) and a coformer as stabilizing excipients. The aim was to introduce a computational approach by preselecting additives using solubility parameter intervals (i.e., overlap range of solubility parameter, ORSP) followed by more advanced COSMO-RS theory modeling. Thus, a mapping of calculated mixing enthalpy and melting points is proposed for in silico evaluation prior to hot melt extrusion. Following experimental testing of process feasibility, the selected formulations were tested for their physical stability using conventional bulk analytics and by confocal laser scanning and atomic force microscopy imaging. In line with the in silico screening, dl-malic and l-tartaric acid (20%, w/w) in HPC formulations showed no signs of early drug crystallization after 3 months. However, l-tartaric acid formulations displayed few crystals on the surface, which was likely a humidity-induced surface phenomenon. Although more research is needed, the conclusion is that the proposed computational small-scale extrusion approach of ternary solid dispersion has great potential in the formulation development of challenging drugs.

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.

The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico - in vitro - in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP- co -vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo , the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo . While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.

Objective: This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties., Significance: While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance., Methods and Results: Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine., Conclusions: The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs.

Objective: The objective of this study was to systematically investigate the impact of lipid composition on the ability to design supersaturated lipid-based drug delivery systems (sLBDDS) using three model drugs with different physico-chemical properties. Significance: This study expands the list of investigated sLBDDS by using alternative vehicle compositions relative to current literature. Methods and results: Drug supersaturation was thermally-induced based on previously reported methods and was successfully achieved for celecoxib and cinnarizine. For the novel drug, JNJ-2A, a lower supersaturation potential was observed for the tested LBDDS. For celecoxib and cinnarizine, crystalline precipitate was observed for some sLBDDS upon storage at 25 °C/65%RH, particularly for medium chain sLBDDS (celecoxib) and long chain sLBDDS (cinnarizine). The greater risk of precipitation observed for celecoxib and cinnarizine, particularly at higher apparent degree of supersaturation (aDS) may be related to their higher crystallization tendency as determined by differential scanning calorimetry. Conclusions: The potential for supersaturation in LBDDS, and the risk of precipitation, was found to be highly drug dependent. The apparent degree of supersaturation was considered a major factor impacting the ability to maintain drug supersaturation upon storage.

Drug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, ε r . Diverse solvents and lipid-based excipients were then experimentally tested for ε r and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an ε r range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained ε r was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Pharmaceutical formulations are complex systems consisting of active pharmaceutical ingredient(s) and a number of excipients selected to provide the intended performance of the product. The understanding of materials' properties and technological processes is a requirement for building quality into pharmaceutical products. Such understanding is gained mostly from empirical correlations of material and process factors with quality attributes of the final product. However, it seems also important to gain knowledge based on mechanistic considerations. Promising is here to study morphological and/or topological characteristics of particles and their aggregates. These geometric aspects must be taken into account to better understand how product attributes emerge from raw materials, which includes, for example, mechanical tablet properties, disintegration or dissolution behavior. Regulatory agencies worldwide are promoting the use of physical models in pharmaceutics to design quality into a final product. This review deals with pharmaceutical applications of theoretical models, focusing on percolation theory, fractal, and multifractal geometry. The use of these so-called fractal approaches improves the understanding of different aspects in the development of solid dosage forms, for example by identifying critical drug and excipient concentrations, as well as to study effects of heterogeneity on dosage form performance. The aim is to link micro- and macrostructure to the emerging quality attributes of the pharmaceutical solid dosage forms as a strategy to enhance mechanistic understanding and to advance pharmaceutical development and manufacturing processes.

Purpose: Lipid suspensions have been shown to be a suitable bio-enabling formulation approach for highly lipophilic or 'grease ball' drug molecules, but studies on 'brick dust' drugs are lacking. This study explored the utility of lipid suspensions for enhancing oral bioavailability of the rather hydrophobic drug nilotinib in vivo in rats., Methods: Four lipid suspensions were developed containing long chain triglycerides, medium chain triglyceride, long chain monoglycerides and medium chain monoglycerides and in vivo bioavailability was compared to an aqueous suspension. Additionally, in vitro lipolysis and wettability tests were conducted., Results: Nilotinib lipid suspensions did not show a bioavailability increase compared to an aqueous suspension. The bioavailability was lower for triglyceride suspensions, relative to both monoglyceride and an aqueous suspension. The long chain monoglyceride displayed a significantly higher bioavailability relative to triglycerides. In vitro lipolysis results suggested entrapment of nilotinib crystals within poorly dispersible triglycerides, leading to slower nilotinib release and absorption. This was further supported by higher wettability of nilotinib by lipids., Conclusion: Monoglycerides improved oral bioavailability of nilotinib in rats, relative to triglycerides. For 'brick dust' drugs formulated as lipid suspensions, poorly dispersible formulations may delay the release of drug crystals from the formulation leading to reduced absorption. Graphical Abstract An aqueous and four lipid suspensions have been evaluated in in vitro and in vivo to gain insights into the potential benefits and limitations of lipid suspensions.

Purpose: The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods., Methods: Atomic force microscopy, inverse gas chromatography and UV surface dissolution imaging were used together for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Fenofibrate and bezafibrate were selected as model drugs in presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively., Results: It was demonstrated that in case of bezafibrate nanosuspension, a surface modification occurred at 37°C compared to 25°C, which notably affected dissolution rate. By contrast, no similar effect was observed in case of fenofibrate nanoparticles., Conclusions: The combined usage of analytical surface methods provides the basis for a better understanding of phenomena that take place on drug surfaces. Such understanding is of importance for pharmaceutical development to achieve desirable quality attributes of nanosuspensions.

Phospholipid-based formulations provide a key technology to formulate poorly water-soluble drugs. A recent interest has been in using phospholipids with a high content of monoacyl phosphatidylcholine (monoacyl PC) due to its ability to form mixed micelles of mono- and di-acylphospholipids upon aqueous dispersion. The present work focused on binary drug- monoacyl PC systems (at about equimolar ratio) with respect to screening of solid dispersion feasibility. It was tested whether or not a molecular rule of thumb can predict the desirable absence of drug crystallinity in the products. Subsequently, molecular simulations were performed to gain a better understanding of molecular association between drugs and monoacyl PC. Finally, the glass-forming ability (GFA) of pure drugs was considered with respect to solid dispersion formation. All products were obtained from a solvent-evaporation process and subsequent analysis of potential drug crystallinity was measured with X-ray powder diffraction and differential scanning calorimetry. Molecular simulations were making use of a Monte Carlo algorithm and molecular properties relevant for GFA were calculated. As a result, the dataset of 28 drugs confirmed an earlier proposed empirical rule that enthalpy of fusion and logP were important for solid dispersion formation, while some relevance was also evidenced for drug energies of frontal orbitals. Interestingly, the Monte Carlo simulations revealed several likely associations between drug and phospholipid rather than a well-defined single complex formation. However, drug-excipient interactions were still pivotal, since GFA of pure drug could not predict solid dispersion formation. These findings led to important molecular insights into binary solid dispersions of drug and monoacyl PC, which can guide formulators in early drug product development., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Practically all medications contain excipients, which are added for the purpose of production enhancement, patient acceptability, improving stability, controlling release etc. Typically excipients are the major components of a drug product, with the active molecule only present in relatively small amounts. Historically, excipients were termed inactive components. However, as highlighted in the present paper; excipients can have an impact on the absorption, distribution, metabolism and elimination (ADME) processes of the co-administered drug, which is important information when selecting excipients for any new formulation. Further, this review also provides a description of the regulatory processes to get new excipients approved in different regions and a discussion of the recent regulatory initiatives, e.g. excipients for paediatric formulations, thereby providing points to consider for the pharmaceutical scientist when selecting excipients for a new drug formulation., (Copyright © 2015. Published by Elsevier B.V.)

Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. β-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of β-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of the present study was to analyze the impact of lipid-based formulation (LBF) dispersion and digestion on the precipitation behavior of weakly basic drugs. Loratadine and carvedilol were formulated in a range of LBFs and drug solubilization was analyzed under simulated dispersive and digestive conditions (fasted state). The extent of supersaturation and drug precipitation as well as the solid-state properties and redissolution behavior of precipitated drugs were assessed. X-ray powder diffraction indicated that carvedilol precipitated in a crystalline form upon dispersion, but interestingly, this drug gave an amorphous precipitate during lipolysis. In contrast, loratadine precipitated as crystalline material during both formulation dispersion and digestion. No influence of the formulation composition on the type of precipitation was observed. These results suggested that in vitro conditions (dispersive versus digestive) largely influenced the solid-state properties of precipitating weak bases. Solid-state characterization of precipitated drugs under different experimental conditions should be routinely performed in formulation screening to better understand the biopharmaceutical behavior of LBFs. Hence, these findings are of high practical importance for the pharmaceutical development and in vitro assessment of LBFs using weakly basic drugs., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Background: An automated version of uniaxial powder flow testing has recently been developed and there is a need for experimental data from pharmaceutical powders., Purpose: To compare the novel testing method with an annular shear cell using different pharmaceutical excipients. A particular aim was to gain an improved understanding of potential differences in the obtained flow results., Methods: Nine excipients were studied with both flow testers at different consolidation levels. Unconfined yield strengths were determined at similar major consolidation stresses. Finally, an anisotropic stress factor was calculated and the fractal character of the powders was assessed by means of image analysis in a rotating drum., Results: Data correlated generally well; however, the unconfined yield strength from uniaxial testing resulted mostly in lower values compared to annular shear cell testing. Differences were specific for the given excipients and mannitol demonstrated the highest discrepancy of measured flow parameters. The differences were first discussed by considering wall friction, anisotropy of forces, brittleness as well as the fractal nature of the powder surface. This heterogeneity of the powder as well as the anisotropy of forces was also found to be important for the relative flow index., Conclusions: The automated uniaxial method demonstrated faster and more reproducible flow testing as compared to an annular shear cell. Therefore, the new method has a high potential in pharmaceutics for example in the quality-control of powders.

Background: Lipid-based drug delivery systems are widely used for enhancing the solubility of poorly water soluble drugs in the gastro-intestinal tract. Following oral intake, lipid systems undergo digestion in the stomach as well as the intestine. Lipolysis is here a complex process at the oil/water interface, influenced by numerous factors., Purpose: To study the digestibility of nine excipients often used in lipid-based drug delivery systems. In addition, we introduced a mathematical model to describe in vitro lipolysis kinetics. A relative lipolysis half life was defined using the reference excipient medium-chain triglycerides., Methods: Using pH-stat equipment, the NaOH consumption was determined in an in vitro lipolysis assay., Results: We identified two classes of excipients. Some additives were partially hydrolysed, whereas other excipients displayed complete lipolysis. For the latter class, a simplified mathematical model provided a good first approximation of initial lipolysis kinetics., Conclusions: Digestion characterization of excipients is important for the development of lipid-based delivery systems. The applied kinetic model and the concept of a relative lipolysis half life seemed to be promising tools for comparing in vitro lipolysis results.

This article focuses on the process analytical technology (PAT) of pharmaceutical dry milling. The first objective is to compare different modes of dynamic image analysis namely, on-line, in-line and at-line for monitoring powder milling. The second objective is to introduce time evolving size and shape analysis (TESSA). Thus, a conical mill was equipped with a dynamic image analysis system which consisted of a xenon flash light and charge-coupled device (CCD) camera. Different pharmaceutical excipients and granulates were chosen as models. The results from the on-line, in-line and the at-line measurement modes showed similar size distributions for the various materials studied, however differences were observed that were mainly attributed to sampling and dispersion. A high correlation of 0.975 (p<0.001) was observed between on-line d(50) and at-line d(50) when compared to 0.917 (p<0.001) between in-line d(50) and at-line d(50). The concept of TESSA was found to be useful in detecting changes in milling conditions including the successful detection of a damaged screen when intentionally introduced in the milling process. This monitoring approach of particle size and shape has potential to reduce product variability, facilitates process development, and ultimately helps in establishing quality by design concept for the manufacture of solid dosage forms., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

The scope of the work is twofold, first to introduce a new avalanche testing instrument and secondly to characterise flowability of pharmaceutical blends comprising of coarse and fine particles. The results were compared with established powder characterisation instruments like the angular shear cell and a flow through orifice tester. These different methods were applied to a broad concentration range of binary mixtures comprising coarse, well-flowing lactose and micronised, poorly flowing albendazole. Some of the mixtures were further analysed with scanning electron microscopy. The results showed clear changes in the flow behaviour of the mixtures that were considered as critical flow concentrations (CFCs). At least three drug concentrations were observed for which the flow behaviour essentially changed. Accordingly, different flow regions were identified, which were explained on the basis of changed particle packing configurations. A theoretical model successfully provided a first estimation of the initial two CFCs. In conclusion, the novel avalanche testing instrument provided complementary information to conventional flowability methodologies, and a thorough assessment of pharmaceutical blends is needed to avoid CFCs in view of a robust formulation development and hence with respect to building quality into the design of the solid dosage forms., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

The scope of the present article is to study formulation parameters of micellar and of lipid delivery systems on the exposure of a new drug compound A in Wistar rats. A statistical analysis is to be performed a posteriori from a data set of all rat studies that were conducted during the preclinical development of the drug. Several formulations were evaluated mainly in view of sufficient exposure in toxicological studies. Because of the low solubility and high lipophilicity of compound A, the preclinical formulation development focused on micellar solutions and different kinds of lipid drug delivery systems. Candidate formulations were first tested for their dilution in artificial intestinal fluids before they were evaluated in the rat. A partial least square model was applied to the entire pharmacokinetic data set, and the type of delivery system, as well as excipients, were investigated in view of effects on the area under the plasma level curve. The results showed that self-emulsifying systems and in particular self-microemulsifying drug delivery systems were most effective in pushing the exposure of compound A. Another significant factor was the dose. A data subset showed nonlinearity in the pharmacokinetics with respect to the dose. However, the most important findings of the multivariate data analysis were overall effects of excipients on the exposure. These effects are considered as a sum of several influences so that the underlying mechanism is essentially complex and is not fully understood. Cremophor and lecithin exhibited a positive effect, whereas TPGS containing systems reached only below average exposure. No significant effect was observed with polysorbate 80 or Solutol HS. The model indicated the favorable use of a cosurfactant, in particular Capmul MCM. Similarly the use of a cosolvent showed a positive coefficient and ethanol was here best in class. No marked effects were observed for the oil selection, but a tendency toward below average exposure was displayed when long-chain triglycerides were in the formulation. The a posteriori analysis of the pharmacokinetic data using multivariate statistical models was very helpful to clarify effects of drug delivery systems as well as of general effects of excipients. Guidance was provided for the formulator, but further studies are needed to better understand the complex effects on a mechanistic level.

Many new drugs exhibit poor wetting behaviour and low aqueous solubility. This is particularly an issue for preclinical studies like toxicological trials, in which considerably higher doses and volumes are being administered compared to clinical studies. Preclinical vehicles typically contain high levels of surfactants that can exert biological effects. However, the biological inertness of vehicles is pivotal for the application in preclinical studies stressing the need in finding new excipients to solve formulation problems of today's drug discovery. The present study investigated the technical feasibility of surfactant-free suspensions using a new poorly soluble drug as model. It was shown that octenyl succinate-modified starches adequately wetted the drug and homogenous tasteless suspensions were obtained. The polymer xanthan gum was identified as macroscopically compatible gelling agent. Concentration effects of xanthan, drug and different modified starches were studied in a D-optimal design with respect to rheological properties. The suspensions were also tested in an analytical centrifuge using NIR transmission profiles to obtain a measure of sedimentation stability under accelerated conditions. The modified starches exhibited only little influence on the viscosity as well as on the yield point in contrast to the rheological effects of xanthan gum. This gelling agent was the main stabilising excipient as the modified starches hindered to a lesser extent sedimentation. The most stable suspensions displayed convenient flow properties. The viscosity at 100 s(-1) and 25 degrees C was in technically acceptable range of 120-140 mPa s in view of a application via gavage or a syringe in animal studies. The results demonstrated that surfactant-free drug suspensions with excellent technical performance can be obtained using octenyl succinate-modified starches. The vehicles were tasteless and based on the experience of modified starches in the food industry, the vehicles should exhibit good tolerability. The future use of such surfactant-free drug suspensions in toxicological, pharmacokinetic and pharmacodynamic studies will have to determine their advantage in terms of biological inertness.

The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of approximately 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40 degrees C/ 50 degrees C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.