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The refined Developability Classification System (rDCS) provides a comprehensive animal-free approach for assessing biopharmaceutical risks associated with developing oral formulations. This work demonstrates practical application of a recently advanced rDCS framework guiding formulation design for six diverse active pharmaceutical ingredients (APIs) and compares rDCS classifications with those of the Biopharmaceutics Classification System (BCS). While the BCS assigns five of the APIs to class II/IV, indicating potentially unfavorable biopharmaceutical attributes, the rDCS provides a more nuanced risk assessment. Both BCS and rDCS assign acetaminophen to class I at therapeutic doses. Voriconazole and lemborexant (both BCS II) are classified in rDCS class I at therapeutic doses, indicating suitability for development as conventional oral formulations. Fedratinib is classified as BCS IV but the rDCS indicates a stratified risk (class I, IIa or IIb), depending on the relevance of supersaturation/precipitation in vivo. Voxelotor and istradefylline (both BCS II) belong to rDCS class IIb, requiring solubility enhancement to achieve adequate oral bioavailability. Comparing the rDCS analysis with literature on development and pharmacokinetics demonstrates that the rDCS reliably supports oral formulation design over a wide range of API characteristics, thus providing a strong foundation for guiding development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Supersaturation and precipitation within the gastrointestinal tract can influence oral absorption of active pharmaceutical ingredients (APIs). Supersaturation of weakly basic APIs upon transfer from the stomach into the small intestine may enhance their absorption, while salt forms of poorly soluble weak acids may generate supersaturated solutions in both stomach and intestine. Likewise, APIs with solubility-limited absorption may be developed as enabling formulations intended to produce supersaturated solutions of the API in the gut. Integrating the supersaturation/precipitation characteristics of the API into the biopharmaceutical risk classification enables comprehensive mapping of potential developability risks and guides formulation selection towards optimizing oral bioavailability (BA). The refined Developability Classification System (rDCS) provides an approach for this purpose. In this work, the rDCS strategy is revisited and a stratified approach integrating the in vitro supersaturation and precipitation behavior of APIs and their formulations is proposed., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The addition of antioxidants to pharmaceutical products is a potential approach to inhibit nitrosamine formation, particularly in solid oral dosage forms like tablets and capsules. The objective was to assess the effect of ten antioxidants on the permeability of four Biopharmaceutics Classification System (BCS) Class III drugs. Bi-directional drug permeability studies in the absence and presence of antioxidants were performed in vitro across MDCK-II monolayers. No antioxidant increased drug permeability, while the positive control sodium lauryl sulfate always increased drug permeability. Results support that any of the ten antioxidants, up to at least 10 mg, can be added to a solid oral dosage form without modulating passive drug intestinal permeability. Additional considerations are also discussed., Competing Interests: Declaration of Competing Interest There are no conflicts of interest for these authors to declare. The information in the paper reflects views from authors and should not be construed to represent FDA's views or policies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In 2010, the Developability Classification System (DCS) was proposed. The DCS was designed to close the gap between the biopharmaceutics classification system, which is aimed at guiding regulatory decisions about well-characterized drugs, and the need for early evaluation of drug candidates with respect to their suitability for oral delivery. The DCS applied solubility in fasted state simulated intestinal fluid to estimate intestinal solubility, assessed the compensatory nature of permeability and solubility during oral absorption and provided a way of estimating the critical the particle size at which dissolution becomes rate-limiting to absorption. Building on this framework, a refined developability classification system (rDCS) is now proposed. The rDCS is stratified into standard investigations applied to all candidates, and customized investigations. Standard investigation of solubility and permeability can be performed according to in-house methods, and the results compared with standard data sets of fasted state human intestinal fluid solubility and human effective jejunal permeability, which have been generated specifically for rDCS. Customized investigations are triggered when there is potential for supersaturation/precipitation (weak bases; salts of weak acids) and to assess dissolution versus permeation limited absorption. In addition, the rDCS offers facile visualization of the results, enabling pragmatic comparison of drug candidates and formulation approaches., (Copyright © 2018. Published by Elsevier Inc.)

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

Poor water solubility of many drugs has emerged as one of the major challenges in the pharmaceutical world. Polymer-based amorphous solid dispersions have been considered as the major advancement in overcoming limited aqueous solubility and oral absorption issues. The principle drawback of this approach is that they can lack necessary stability and revert to the crystalline form on storage. Significant upfront development is, therefore, required to generate stable amorphous formulations. A thorough understanding of the processes occurring at a molecular level is imperative for the rational design of amorphous solid dispersion products. This review attempts to address the critical molecular and thermodynamic aspects governing the physicochemical properties of such systems. A brief introduction to Biopharmaceutical Classification System, solid dispersions, glass transition, and solubility advantage of amorphous drugs is provided. The objective of this review is to weigh the current understanding of solid dispersion chemistry and to critically review the theoretical, technical, and molecular aspects of solid dispersions (amorphization and crystallization) and potential advantage of polymers (stabilization and solubilization) as inert, hydrophilic, pharmaceutical carrier matrices. In addition, different preformulation tools for the rational selection of polymers, state-of-the-art techniques for preparation and characterization of polymeric amorphous solid dispersions, and drug supersaturation in gastric media are also discussed., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The need for solubility enhancement through formulation is a well-known but still problematic issue because of the numbers of poorly water-soluble drugs in development. There are several possible routes that can be taken to increase the bioavailability of drugs intended for immediate-release oral formulation. The best formulation strategy for any given drug will depend on numerous factors, including required dose, shelf life, manufacturability, and the properties of the active pharmaceutical ingredient (API). Choosing an optimal formulation and manufacturing route for a new API is therefore not a straightforward process. Currently, there are several approaches that are used in the pharmaceutical industry to select the best formulation strategy. These differ in complexity and efficiency, but most try to predict which route will best suit the API based on selected molecular parameters such as molecular weight, lipophilicity (logP), and solubility. These methods range from using no tools, trial and error methods through a variety of complex tools from small in vitro or in vivo experiments or high throughput screening, guidance maps, and decision trees to the most complex methods based on computational modelling tools. This review aims to list available support tools and explain how they are used., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The ability to predict in vivo response of an oral dosage form based on an in vitro technique has been a sought after goal of the pharmaceutical scientist. Dissolution testing that demonstrates discrimination to various critical formulations or process attributes provides a sensitive quality check that may be representative or may be overpredictive of potential in vivo changes. Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in vivo predictability. To establish this in vitro-in vivo link, a clinical study must be performed. In this article, recommendations are given in the selection of batches for the clinical study followed by potential outcome scenarios. The investigation of a Level C in vitro-in vivo correlation (IVIVC), which is the most common correlation for immediate-release oral dosage forms, is presented. Lastly, an IVIVC case study involving a biopharmaceutical classification system class IV compound is presented encompassing this strategy and techniques., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition classification system (BDDCS). To better understand the applicability of the biowaiver, we carried out a cross-sectional survey to estimate the relative risk of obtaining nonbioequivalent (non-BE) or bioinequivalent (BIE) results for drug products containing drugs belonging to each of the biopharmaceutics classification system (BCS) and BDDCS classes. Five hundred bioequivalence studies were randomly sampled from a database of the Brazilian Health Surveillance Agency (ANVISA). The drugs were classified according to the BCS and BDDCS, to evaluate how characteristics related to drug and dosage form influence the outcome of bioequivalence studies. The relative risk of obtaining a non-BE result was approximately four times lower for drugs in classes 1 and 3 of BCS or BDDCS when compared with class 2 drugs. Thus, it seems that the final outcome of a bioequivalence study is strongly influenced by the solubility of the drug, but not by its intestinal permeability or extent of metabolism., (Copyright © 2013 Wiley Periodicals, Inc.)

Biopharmaceutics Classification System and Biopharmaceutics Drug Distribution Classification System are complimentary, not competing, classification systems that aim to improve, simplify, and speed drug development. Although both systems are based on classifying drugs and new molecular entities into four categories using the same solubility criteria, they differ in the criterion for permeability and have different purposes. Here, the details and applications of both systems are reviewed with particular emphasis of their role in drug development., (Copyright © 2012 Wiley Periodicals, Inc.)

The objective of this study was to evaluate the suitability and acceptance criteria of isolated rat jejunum model for Biopharmaceutics Classification System (BCS)-permeability classification. The evaluation followed recommended procedures including investigation of tissue integrity by applying damage triggers (nitrogen gassing, elevated temperature, azide addition), characterization of transporter functionality, and expression and development of correlation between rats' apparent permeability coefficient (P(app) ) versus humans' and versus oral fraction absorbed (f(a) ) in humans. Firstly, damage triggers caused a decrease in transepithelial resistance and potential difference and increase in lucifer yellow (LY) and fluorescein isothiocyanate (FITC)-dextran P(app) . However, only FITC-dextran P(app) 's increase was considered significant in all treatment groups, making FITC-dextran a better indicator of jejunum integrity than LY. Secondly, the expression level of selected intestinal transporters highly correlated between rat and human and functionality of P-glycoprotein was confirmed. P(app) of investigated drugs correlated with human f(a) (R(2) = 0.85, n = 20) and with human permeability coefficients (R(2) = 0.86, n = 13). Utility of described model for BCS classification was shown on levetiracetam, where significantly higher permeability of levetiracetam as compared with internal standard metoprolol was determined (t-test, p = 0.005). In conclusion, isolated rat jejunum model is a useful tool not only for mechanistic investigation, but also for permeability classification according to BCS and consequently for BCS-based biowaiver procedures., (Copyright © 2012 Wiley Periodicals, Inc.)

This review presents a general overview about the amperometric detection potentialities associated to flow injection analysis (FIA). Fundamental aspects, developments, applications and advantages accrued from the coupling of voltammetry with FIA for pharmaceutical analyses are discussed. The selected references present several examples for this association in various classes of drugs and support their advantages. Examples illustrate that the amperometric techniques coupled with flow system can usually be used in drug routine analysis without sample pretreatment. Amperometry/FIA has proved to be an excellent alternative to the chromatographic techniques and it has been used in routine analysis, from the simplest analytes to more complex species, solving even special cases such as the enantiomeric analysis of pharmaceutical compounds with a chiral moiety, which requires time-consuming sample preparation or expensive instrumentation. This revision also aims to contribute for reducing the gap between the vast possibilities enabled by electroanalytical techniques and their effective utilization for pharmaceutical analysis., (© 2010 Wiley-Liss, Inc. and the American Pharmacists Association)

A revised classification system for oral drugs was developed using the biopharmaceutics classification system (BCS) as a starting point. The revised system is designed to have a greater focus on drug developability. Intestinal solubility, the compensatory nature of solubility and permeability in the small intestine and an estimate of the particle size needed to overcome dissolution rate limited absorption were all considered in the revised system. The system was then validated by comparison with literature on the in vivo performance of a number of test compounds. Observations on the test compounds were consistent with the revised classification, termed the developability classification system (DCS), showing it to be of greater value in predicting what factors are critical to in vivo performance than the widely used BCS., (© 2010 Wiley-Liss, Inc. and the American Pharmacists Association)

Currently, the EMEA, FDA, and WHO as regulatory authorities accept rapidly dissolving (>85% dissolved in 30 min) biopharmaceutics classification system (BCS) I drug products for biowaiver candidates. In the draft EMEA guideline the requirement has been set tighter, that is, the drug product should be very rapidly dissolving (>85% dissolved in 15 min) to be eligible for a biowaiver. Pharmacokinetic modeling of 32 BCS I drugs was performed to demonstrate that very rapid dissolution is not necessary to guarantee bioequivalence for them. Rapid dissolution and similar dissolution profiles are sufficient criteria for all BCS I drugs., ((c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association.)

The aim of this review is to describe the theoretical background lying behind the solid drug mechanochemical activation by cogrinding pointing out its advantages and drawbacks. A brief historical introduction precedes the discussion about the mechanisms leading to solid drug activation. This allows to clarify the concept of solid activation whose main effect is to improve drug solubility and, thus, drug bioavailability. Then, the attention is focused on the experimental tools used to evaluate drug activation before the in vivo use. This, of course, permits to properly modulate the milling conditions (milling time, mill revolution speed, drug/carrier ratio and so on) in the light of the optimisation of milling process and activated system properties. Thereafter, the discussion shifts on the different kinds of mills that can be used and on mills classification based on the energy transferred to the materials. Fundamental tool to perform this task is the mathematical modelling of mill dynamics that is here shown for different mills kinds. Finally, some examples of activated systems performance both in vitro and in vivo are presented and discussed. In conclusion, mechanochemical activation improves drug bioavailability. Interestingly, this activation does not require the use of solvents whose elimination from the activated product can be difficult and expensive but a relatively simple mechanical treatment. On the other hand, this approach, usually, works only for poorly water soluble drugs (solubility <100 microg/mL) that do not exhibit permeability problems., ((c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association)

This study presents a mechanistic QSAR analysis of human intestinal absorption of drugs and drug-like compounds using a data set of 567 %HIA values. Experimental data represent passive diffusion across intestinal membranes, and are considered to be reasonably free of carrier-mediated transport or other unwanted effects. A nonlinear model was developed relating %HIA to physicochemical properties of drugs (lipophilicity, ionization, hydrogen bonding, and molecular size). The model describes ion-specific intestinal permeability of drugs by both transcellular and paracellular routes, and also accounts for unstirred water layer effects. The obtained model was validated on two external data sets consisting of in vivo human jejunal permeability coefficients (P(eff)) and absorption rate constants (K(a)). Validation results demonstrate good predictive power of the model (RMSE = 0.35-0.45 log units for log K(a) and log P(eff)). High prediction accuracy together with clear physicochemical interpretation (log P, pK(a)) makes this model particularly suitable for use in property-based drug design., ((c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association)

This study presents a mechanistic QSAR analysis of passive blood-brain barrier permeability of drugs and drug-like compounds in rats and mice. The experimental data represented in vivo log PS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 log PS values was compiled. A subset of 178 compounds was assumed to be driven by passive transport that is free of plasma protein binding and carrier-mediated effects. This subset was described in terms of nonlinear lipophilicity and ionization dependences, that account for multiple kinetic and thermodynamic effects: (i) drug's kinetic diffusion, (ii) ion-specific partitioning between plasma and brain capillary endothelial cell membranes, and (iii) hydrophobic entrapment in phospholipid bilayer. The obtained QSAR model provides both good statistical significance (RMSE < 0.5) and simple physicochemical interpretations (log P and pKa), thus providing a clear route towards property-based design of new CNS drugs., ((c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association)

A rapid solubility-screening assay was developed with a focus on Biopharmaceutic Classification Scheme (BCS) class II drug solubility in animal and simulated human gastrointestinal (GI) fluids. The assay enables biologically promising drug leads to be evaluated for solubility limitations earlier in the drug development process, minimizes GI fluid needs, and produces in vitro solubility information with potential in vivo implications. A number of BCS II drugs were dissolved in DMSO at approximately 40 mM, and robotically distributed to a 96-well plate. The DMSO was evaporated and drugs were equilibrated with selected GI fluids, both fed and fasted states. After equilibration, precipitated wells were subjected to HPLC analysis. A spreadsheet calculated solubility automatically from HPLC output. Intra-day, inter-day, and inter-plate reproducibility were within 15% RSTD for the tested drugs with the primary source of variability being injection precision of our injector system. The reported solubility from screening assays was well correlated with literature data (r(2) = 0.80) with a slope of 0.86 and (r(2) = 0.99) with a slope of 0.89. This screening assay converts conventional solubility measurements to a 96-well format for increased throughput (>12 samples/h), reduces fluid needs, and minimizes drug consumption., (2007 Wiley-Liss, Inc)

A topological substructural molecular design approach (TOPS-MODE) has been used to predict whether a given compound is a P-glycoprotein (P-gp) substrate or not. A linear discriminant model was developed to classify a data set of 163 compounds as substrates or nonsubstrates (91 substrates and 72 nonsubstrates). The final model fit the data with sensitivity of 82.42% and specificity of 79.17%, for a final accuracy of 80.98%. The model was validated through the use of an external validation set (40 compounds, 22 substrates and 18 nonsubstrates) with a 77.50% of prediction accuracy; fivefold full cross-validation (removing 40 compounds in each cycle, 80.50% of good prediction) and the prediction of an external test set of marketed drugs (35 compounds, 71.43% of good prediction). This methodology evidenced that the standard bond distance, the polarizability and the Gasteiger-Marsilli atomic charge affect the interaction with the P-gp; suggesting the capacity of the TOPS-MODE descriptors to estimate the P-gp substrates for new drug candidates. The potentiality of the TOPS-MODE approach was assessed with a family of compounds not covered by the original training set (6-fluoroquinolones), and the final prediction had a 77.7% of accuracy. Finally, the positive and negative substructural contributions to the classification of 6-fluoroquinolones, as P-gp substrates, were identified; evidencing the possibilities of the present approach in the lead generation and optimization processes., (Copyright 2006 Wiley-Liss, Inc. and the American Pharmacists Association.)

This project compared the effect of formulation variables on the dissolution performance of model Biopharmaceutics Classification System (BCS) Class II drugs from hard gelatin capsules using statistical analysis and Bayesian networks. The drugs chosen for this study were carbamazepine (CAR), chlorpropamide (CHL), diazepam (DIA), ketoprofen (KET), and naproxen (NAP). Formulations contained anhydrous lactose, microcrystalline cellulose, sodium stearyl fumerate, sodium lauryl sulfate, and croscarmellose sodium. A Box-Behnken experimental design was used in the statistical analysis. The weakly acidic drugs were tested using USP apparatus II with capsule sinkers in 0.1M pH 6.8 Potassium Phosphate buffer. The weakly basic drugs were tested using USP apparatus I in 0.1N HCl buffer. Mean dissolution profiles were compared via calculation of the similarity factor. The Box-Behnken experimental design was found to be useful in assessing primary and secondary excipient effects on dissolution. The Bayesian Network developed for the dataset mirrored the key excipient effects on dissolution performance., ((c) 2005 Wiley-Liss, Inc.)

Rapid methods for ranking the solubility of compounds in aqueous media using commercial, 96-well ultraviolet-visible (UV-vis) and nephelometric plate readers are described. The methods were evaluated using commercially available compounds from a variety of structural classes as well as a series of structurally related compounds derived from combinatorial synthesis. Samples were predissolved in dimethyl sulfoxide (DMSO) and then added to the study solvent to attain a final concentration of DMSO in the aqueous solution of 5%. Comparison of filtration of the samples through nylon and poly(tetrafluoroethylene) (PTFE) membranes is also described. The solubility of the compounds determined using the UV-vis plate reader in the absorption mode (with samples filtered with the PTFE filter) as well as in the light scattering mode was in good agreement with that determined by high-performance liquid chromatography, with an average correlation of 0.95. Solubility data obtained using a 96-well nephelometer was also comparable (r(2) = 0.97). The nonequilibrium methods described in this study can be used to rapidly rank compounds from combinatorial libraries for solubility and can also give a general assessment of solubility prior to running additional high throughput screens in a drug discovery environment., (Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:521-529, 2001)

A simple form of pattern recognition is successfully used to classify a set of structurally diverse therapeutic agents. By using only organic structural information, the major pharmacological classes present were correctly identified and the pharmacologically unrelated compounds were separated out. One technique of factor analysis--principal component analysis--is shown to be readily adaptable in preprocessing the data. Simple graphical representation of the results enables their direct interpretation.