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Original Research

Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development

, &
Pages 1563-1575 | Published online: 24 Sep 2014

Abstract

The main objective of this work was to investigate in-silico predictions of physicochemical properties, in order to guide oral drug development by provisional biopharmaceutics classification system (BCS). Four in-silico methods were used to estimate LogP: group contribution (CLogP) using two different software programs, atom contribution (ALogP), and element contribution (KLogP). The correlations (r 2) of CLogP, ALogP and KLogP versus measured LogP data were 0.97, 0.82, and 0.71, respectively. The classification of drugs with reported intestinal permeability in humans was correct for 64.3%–72.4% of the 29 drugs on the dataset, and for 81.82%–90.91% of the 22 drugs that are passively absorbed using the different in-silico algorithms. Similar permeability classification was obtained with the various in-silico methods. The in-silico calculations, along with experimental melting points, were then incorporated into a thermodynamic equation for solubility estimations that largely matched the reference solubility values. It was revealed that the effect of melting point on the solubility is minor compared to the partition coefficient, and an average melting point (162.7°C) could replace the experimental values, with similar results. The in-silico methods classified 20.76% (±3.07%) as Class 1, 41.51% (±3.32%) as Class 2, 30.49% (±4.47%) as Class 3, and 6.27% (±4.39%) as Class 4. In conclusion, in-silico methods can be used for BCS classification of drugs in early development, from merely their molecular formula and without foreknowledge of their chemical structure, which will allow for the improved selection, engineering, and developability of candidates. These in-silico methods could enhance success rates, reduce costs, and accelerate oral drug products development.

Introduction

Oral administration is the most comfortable and widespread route of drug intake. Indeed, the majority of drug products worldwide are oral dosage forms.Citation1,Citation2 This makes gastrointestinal (GI) absorption a determining factor in the successful development of candidate bioactive molecules into marketable drug products. In 1995, Amidon et al introduced the Biopharmaceutics Classification System (BCS) as a scientific paradigm for drug absorption analyses.Citation3 In principle, the BCS identified the solubility of the drug in the GI milieu, and its permeability across the intestinal epithelium, as the two key parameters in the intestinal absorption process.Citation4Citation7 The BCS is often referred to in the context of drug regulation, as it was adopted by the US Food and Drug Administration (FDA) and European Medicines Association (EMA) as the basis for granting oral drug product manufacturers waivers from in-vivo bioequivalence studies.Citation8,Citation9 While the importance of biowaivers for cost reduction of drug products is undisputed, it is arguable that the BCS can be of even greater use in the development of new molecular entities (NMEs) into marketable drug products.Citation10Citation12 Early BCS classification would allow selection and engineering of candidate molecules with favorable biopharmaceutical properties from the general pool, and selection of suitable polymorphic forms and salts. It may also indicate the strategy that should be adopted in formulation development, in order to improve the absorption of a candidate drug.Citation2,Citation11,Citation13,Citation14

BCS classification requires knowledge of a candidate’s solubility and permeability. Solubility can be estimated using established in-vitro methods such as the shake flask method.Citation15Citation18 Permeability is ideally estimated by perfusion of intestinal segments in humans.Citation19Citation21 However, these experiments are complicated, costly, and require the exposure of healthy human volunteers to drugs. Alternatively, permeability may be estimated using validated cell culture methods or animal intestinal perfusion studies.Citation22Citation25 Both solubility and permeability estimations require synthesis and formulation of the drug, which are not available at early development phases, and are costly and time-consuming processes. It was therefore suggested that drugs can be provisionally classified by the BCS according to physicochemical estimations rather than by experiments.Citation5,Citation12,Citation26Citation28 The main objective of this work was to study the utility of in-silico predictions of physicochemical properties, in order to guide the estimations of permeability, solubility and early BCS classification of drugs. The BCS classification was also compared to the Biopharmaceutics Drug Disposition Classification System (BDDCS).Citation29 Our results demonstrate that in-silico calculations of physicochemical properties are useful for the early classification of drugs according to the BCS, thus may be extremely useful in the research and development (R&D) process of oral drug products.

Methods

Drug dataset

The World Health Organization (WHO) Model List of Essential Medicines, as well as lists of the most-sold drugs in Great Britain (GB), Israel (IL), Japan (JP), South Korea (KR), Spain (ES) and the United States (US) were used as sources for the drug database in our study. From these national lists, drugs were chosen for the compiled database in the study if they met the following two criteria: 1) immediate release solid oral dosage form; and 2) highest dose strength on the lists. Drug selection was from databases available at the following Internet web sites: www.fda.gov, www.medicines.org.uk, www.health.gov.il, www.portalfarma.com, jpora452.rsjp.net, www.kimsonline.co.kr, ezdrug.mfds.go.kr, and www.who.int.

Octanol/water partition coefficients

The partition coefficients between n-octanol and water for the unionized form of the drugs (LogP) were estimated based on several approaches. The BioLoom 5.0 software (BioByte, Claremont, CA, USA) provides a large database of empirical measurements of LogP (MLogP) from which relevant values for our drug dataset were obtained. This software, along with ChemDraw Ultra 8.0 software (CambridgeSoft, Cambridge, MA, USA) was also utilized for theoretical calculations of LogP, using algorithms based on the contributions of functional groups (CLogP) as developed and described by Hansch and Leo.Citation30,Citation31 Drug chemical structures were taken from the Merck Index.Citation32 Moreover, LogP values were calculated using the Molecular Operating Environment (MOE) Version 2004.03 (Chemical Computing Group, Montreal, Quebec, Canada) developed by Crippen and Wildman, which is based on atomic contribution to hydrophobicity (ALogP).Citation33,Citation34 Finally, a simplified algorithm which relies on element contribution (KLogP) was derived merely from the drug’s molecular formula, while disregarding its chemical structure. The number of repetitions of each of the elements (eg, C, H, N, O, F, P, S, Cl, and Br) that are commonly present in organic compounds was calculated for the drugs on the compiled dataset, then fitted against the experimental MLogP by linear regression using the Microsoft Office Excel 2010 “LINEST” function, resulting in the equation:

KLogP=(nH×H)+(nC×C)+(nN×N)+(nO×O)+(nF×F)+(nP×P)+(nS×S)+(nCl×Cl)+(nBr×Br)
where ni = number of type i atoms, and i is the partial contribution of the element: H =−0.0060, C =0.2463, N =−0.3163, O =−0.4515, F =−0.1033, P =−0.7753, S =0.0450, Cl =0.6534, and Br =−0.2781.

Correlation of partition coefficients with human jejunal permeability

The classification of the permeability was validated based on correlations between human intestinal permeability for 29 reference drugs Citation19Citation21,Citation28,Citation35 and the above-mentioned partition coefficients (CLogP, AlogP, or KLogP). Metoprolol was selected as the marker compound for permeability, since fraction dose absorbed of 95% was previously demonstrated.Citation36Citation38 Hence, drugs that were similarly categorized by both partition coefficients values and human intestinal permeability (high/high or low/low respectively, with regards to metoprolol) are considered to be correctly classified, while drugs that were categorized as low/high and high/low by the two methods are termed false negatives and false positives, respectively.

Solubility

Literature solubility

Drug solubility data (mg/mL) were taken from the Merck Index,Citation32 the United States Pharmacopeia (USP),Citation39 the KFDA ezDrug Information, and the Japanese prescription information (available at the above-mentioned websites). Whenever significant dissimilarities were found between the above sources, the lowest value was selected for the calculations of dose number. For many drugs, the above-mentioned sources provide only a literal description rather than a specific value of solubility. In such cases, we adopted the USP solubility categorization () and estimated the solubility to be the lower limit of the relevant solubility range. Drugs listed as practically insoluble (pi) were assigned using a more conservative value of 0.01 mg/mL rather than the USP definition of 0.1 mg/mL.

Table 1 Solubility definitions

In-silico solubility of the drugs

The lipophilicity of a drug is inversely correlated to its aqueous solubility. This well-known fact was instrumental to the development of the thermodynamic equation for solubility of non-electrolytes in water by Amidon and Williams:Citation40

LogCs=1.050.0099MPPC
where Cs is the molar aqueous solubility of the drug at 25°C, MP is the melting point (in °C) for the uncharged form of the drug molecule, and PC is the partition coefficient.

By placing in-silico partition coefficient estimations (CLogP, AlogP, or KLogP) in the equation, we were able to calculate the solubility for a total of 185 drugs on the dataset for which melting points were measured.

Calculations of dose number

The dimensionless dose-normalized solubility, dose number (D0), was calculated using the equation

D0=(M0/V0)Cs
where M0 is the maximum dose strength (mg), Cs is either the reference or in-silico estimated solubility (mg/mL), and V0 =250 mL, based on the FDA recommendation to take solid oral drug forms with a full glass of water.

Drugs with D0 ≤1 were classified as high-solubility, and vice versa.

Results

Correlation between experimental and in-silico partition coefficients

The measured (MLogP) and calculated partition coefficients for 154 drugs are listed in Table S1 (available from: http://www.dovepress.com/cr_data/supplementary_file_68909_1.pdf). Excellent correlations were obtained between either BioLoom 5.0 (BioByte, Claremont, CA, USA) or ChemDraw 8.0 (Perkin–Elmer, Cambridge, MA, USA) CLogP estimations and the measured values (r 2=0.97). Good correlation with measured partition coefficients were also obtained with in-silico ALogP (r 2=0.82). Lower yet acceptable correlation was obtained also with KLogP, which is based exclusively on molecular formula without information of the chemical structure (r 2=0.71).

Human permeability and partition coefficient correlation

The experimentally-measured human jejunal permeability data for 29 drugs, and the in-silico partition coefficient values, appear in Table S2 (available from: http://www.dovepress.com/cr_data/supplementary_file_68909_2.pdf) and are depicted in . Classification using the various methods was similar and correct for 19–21 drugs (64.3%–72.4%). The data show that the classification of passively-absorbed drugs was generally correct. However, the permeability of polar drugs that are known to be absorbed via carrier-mediated mechanisms, such as cephalexin,Citation41,Citation42 enalapril,Citation43 levodopa,Citation44 L-leucine,Citation44,Citation45 phenylalanine,Citation46,Citation47 and valacyclovirCitation48,Citation49 tended to be underestimated using partition coefficient. On the other hand, false high-permeability classification was obtained for losartanCitation50,Citation51 which is a substrate for efflux transporters (false positives). presents the permeability classification using the different in-silico methods versus human jejunal permeability when the seven drugs that are known substrates for transporters were omitted from the analysis. It can be seen that the accuracy of the predictions was improved to 81.8%–90.9%.

Figure 1 Correlation of permeability classification using the different in-silico partition coefficients versus human jejunal permeability for 29 drugs.

Abbreviation: MOE, Molecular Operating Environment.
Figure 1 Correlation of permeability classification using the different in-silico partition coefficients versus human jejunal permeability for 29 drugs.

Figure 2 Correlation of permeability classification using the different in-silico partition coefficients versus human jejunal permeability for 22 drugs, following exclusion of drugs with known involvement of active influx/efflux transport processes in their intestinal absorption.

Abbreviation: MOE, Molecular Operating Environment.
Figure 2 Correlation of permeability classification using the different in-silico partition coefficients versus human jejunal permeability for 22 drugs, following exclusion of drugs with known involvement of active influx/efflux transport processes in their intestinal absorption.

Permeability, solubility, and provisional BCS classification

Permeability classification

illustrates the permeability classification of 363 drugs by comparing their CLogP, ALogP or KlogP values (1.49, 1.61, and 1.87, respectively) to those of metoprolol. The various in-silico partition coefficients produced similar permeability classifications; 57.02%–62.53% and 36.36%–39.94% of the drugs were classified as high- and low-permeability, respectively.

Figure 3 Permeability classification of 363 drugs using the different in-silico partition coefficients.

Abbreviation: MOE, Molecular Operating Environment.
Figure 3 Permeability classification of 363 drugs using the different in-silico partition coefficients.

Solubility classification

The in-silico partition coefficient calculations and melting point data were used to estimate the solubility of 185 drugs. The maximum dose strengths, melting points, reference solubility, CLogP (BioLoom 5.0), KLogP, and the in-silico dose number (D0) calculated with both methods are listed in Table S3 (available from: http://www.dovepress.com/cr_data/supplementary_file_68909_3.pdf). The solubility categorization () based on the various in-silico estimations versus literature solubility data are shown in . In general, solubility estimations with the various partition coefficients matched the reference solubility values. However, solubility estimations based on KLogP significantly underestimated the number of practically insoluble drugs, and overestimated the number of very slightly soluble drugs (~19% difference). It is noteworthy that in-silico solubility estimations with the average melting point (162.7°C) versus experimental melting points produced similar results, with a maximal difference of ~6%. depicts a theoretical plot of the dependency of solubility on partition coefficient and melting point. It is evident from the figure that the effect of melting point on the solubility is very small compared to the effect of LogP. This theoretical plot explains the similar solubility categorization obtained with experimental versus average melting point, shown in , indicating that the use of average melting point value in solubility estimations may not lead to significant loss of accuracy.

Figure 4 Solubility estimations of 185 drugs using the different in-silico partition coefficients and experimental melting points or average melting point.

Abbreviation: MOE, Molecular Operating Environment.
Figure 4 Solubility estimations of 185 drugs using the different in-silico partition coefficients and experimental melting points or average melting point.

Figure 5 Theoretical plot of the dependency of solubility on LogP and melting point.

Figure 5 Theoretical plot of the dependency of solubility on LogP and melting point.

Solubility BCS classification was assigned for a given drug according to its dose number (D0), which was calculated using the maximal dose. This puts a theoretical limitation on the early assignment of the BCS solubility class, as the dosage range of any drug can only be assessed later on. plots the dependency of the dose number on solubility and the maximal dose. This plot reveals that in the maximal dose range commonly found for drugs and drug-like molecules (0.005–1,000 mg) any solubility value above 10 mg/mL would indicate a dose number ≤1, and hence a BCS high-solubility classification. Hence for solubility categories very soluble, freely soluble, soluble, and slightly soluble drugs (), a BCS high-solubility classification can be assigned. For drugs with lower solubility values, a theoretical dosage range can be used for the provisional solubility classification, as was previously shown.Citation12,Citation52

Figure 6 Theoretical plot of the dependency of dose number (D0) on the solubility and the maximal dose.

Figure 6 Theoretical plot of the dependency of dose number (D0) on the solubility and the maximal dose.

Provisional BCS classification

Provisional BCS classifications with the different in-silico methods are listed in Table S4 (available from: http://www.dovepress.com/cr_data/supplementary_file_68909_4.pdf) and shown in . The distribution of LogP, melting point, and maximal dose was analyzed for drugs classified by the CLogP (BioLoom 5.0) and KLogP methods, and illustrated in . The classification and distribution of drug properties in each BCS class as defined by Amidon et alCitation3 are presented in . It can be seen that the classification using the different approaches produced comparable results: on average, 20.76% (±3.07%) of drugs were classified as Class 1, 41.51% (±3.32%) as Class 2, 30.49% (±4.47%) as Class 3, and 6.27% (±4.39%) as Class 4. LogP values of drugs from Class 1–2 were higher than Class 3–4, and the distribution of values was narrower in Class 1 and Class 4 compared to Class 2 and 3 (). Melting point values had quite similar distributions in Class 1, Class 2, and Class 3, between the first and third quartiles (~107°C–208°C). The melting point values of Class 4 drugs were distributed in a significantly higher range, ~170°C–270°C (). Maximal dose range between the first and third quartiles was the lowest for Class 1 drugs (~1–10 mg), medium for Classes 2 and 3 (~25–250 mg), and highest for Class 4 drugs, with values ~300–600 mg ().

Figure 7 Provisional BCS classification of 185 drugs based on the different in-silico partition coefficients and experimental melting points or average melting points.

Abbreviation: MOE, Molecular Operating Environment; BCS, Biopharmaceutics Classification System.
Figure 7 Provisional BCS classification of 185 drugs based on the different in-silico partition coefficients and experimental melting points or average melting points.

Figure 8 Distributions of drug properties in each BCS class (provisional classification with CLogP [BioLoom 5.0] or KLogP): (A) LogP; (B) melting point; and (C) maximal dose.

Abbreviation: BCS, Biopharmaceutics Classification System.
Figure 8 Distributions of drug properties in each BCS class (provisional classification with CLogP [BioLoom 5.0] or KLogP): (A) LogP; (B) melting point; and (C) maximal dose.

Figure 9 The BCS as defined by Amidon et alCitation3 and the classification and distribution of drug properties in each BCS class.

Abbreviation: BCS, Biopharmaceutics Classification System.
Figure 9 The BCS as defined by Amidon et alCitation3 and the classification and distribution of drug properties in each BCS class.

BDDCS and in-silico partition coefficient

We examined the correlation between our in-silico BCS classification and the BDDCS-based classification for 140 drugsCitation29 and the results are shown in . The BDDCS classified more drugs as Class 1 and fewer drugs as Class 3 in comparison to the provisional in-silico BCS classification (~10% difference). This observation may be attributed to the lower cutoff point (70%) used by Benet for metabolism, compared to the overly conservative permeability standard (metoprolol).Citation38,Citation53

Figure 10 Provisional BCS classification with in-silico methods (average) of 140 drugs versus their BDDCS classification.

Abbreviations: BCS, Biopharmaceutics Classification System; BDDCS, Biopharmaceutics Drug Disposition Classification System.
Figure 10 Provisional BCS classification with in-silico methods (average) of 140 drugs versus their BDDCS classification.

Discussion

Permeability classification

It has been shown before that the permeability of drugs can be predicted in-silico using calculable physicochemical drug properties. Kasim et al estimated the permeability of 123 immediate release oral drug products listed in the WHO List of Essential Drugs using octanol/water partition coefficient calculations.Citation54 This work was later extended by Takagi et al to include the most popular oral immediate release drug products in the United States, Great Britain, Spain and Japan.Citation55 The CLogP is a well-established and accurate method to assess the octanol/water partition coefficient (LogP). However, this algorithm demands foreknowledge of several intramolecular factors, including hydrogen bonding interactions and electronic and steric effects. In this work, In addition to CLogP, we used a simpler atomic LogP method, ALogP, that allowed some intramolecular factors to be neglected. More importantly, we examined the simplified KLogP method to calculate LogP, that is based solely on the molecular formula of the drug, while disregarding its chemical structure.

Provisional permeability classification using all four different in-silico approaches had comparable accuracy versus human jejunal permeability of 29 drugs (64.3%–72.4% correct classifications) as illustrated in . In general, drugs that permeate the intestinal wall chiefly via passive transcellular diffusion were assigned the correct permeability classification by the different in-silico partition coefficients. In contrast, in-silico approaches failed to classify the permeability of drugs that were recorded as having significant involvement of active transport processes (either influx or efflux) in their absorption. Indeed, when such drugs were excluded from the analysis, accuracy was significantly improved (81.82%–90.91%, ). It is evident from these results that while passive permeability can be accurately predicted with in-silico LogP calculations, a separate module should be included in future intestinal permeation models in order to account for carrier-mediated processes.

Similar permeability classifications were obtained with the various algorithms for the 363 drugs on the database, with a maximal difference of ~5% (). The results suggest that the simplified KLogP estimations are as reliable as the more sophisticated methods for provisional permeability classification.

The simplified approach chosen in this work was not without its limitations. First, in-silico approaches generally failed to classify the permeability of drugs that are actively absorbed via transporters (). This was to be expected, as carrier-mediated processes depend on specific drug–protein interactions rather than lipophilicity. Moreover, our model did not account for other factors that may affect absorption, such as segmental-dependent permeability. Evidently, future models will have to be able to capture the full complexity of the intestinal tract in order to minimize the risk of false negative and false positive predictions, both of which may result in inappropriate development strategies and allocation of resources.

Solubility classification

Solubility can be experimentally determined more readily than permeability by using established in-vitro studies such as the shake flask method. However, such methods still require synthesis of the compound, which is often complicated, time consuming, costly, and may be futile if the molecule proves to be inadequate for further development. Therefore, we estimated the solubility of the drugs in our dataset using the inverse correlation between the lipophilicity of a drug and its molar solubility as described by Amidon and Williams.Citation40 We chose this simplified approach over more complex models in order to demonstrate that reliable early BCS classification of drugs can be achieved even with minimal input data. The solubility estimations of 185 drugs with the various partition coefficients generally matched the reference solubility values. However, solubility estimations based on KLogP significantly underestimated the number of practically insoluble drugs and overestimated the number of very slightly soluble drugs (~19% difference, as shown in ). These results indicate that more sophisticated approaches for the estimation of LogP, and possibly additional physicochemical properties, are required for more refined estimations of borderline solubility.

In addition to the partition coefficient, solubility in-silico estimations require foreknowledge of the melting point. This puts a theoretical limitation on early solubility estimation, as currently, the melting point must be empirically measured. However, our theoretical plot of the dependency of solubility on partition coefficient and melting point () revealed that the effect of the melting point is minor in comparison to the partition coefficient, suggesting that the average melting point may be used as a substitute for the measured melting point in solubility estimations without significant loss of accuracy. Indeed, solubility estimations using the average melting point value (162.7°C) versus experimental melting points produced similar results, with a maximal difference of ~6% (). Recent works suggest that melting point values can also be calculated in-silico. While current methods for melting point calculations are still limited, such algorithms may be incorporated to solubility models in the future, further refining them and allowing for accurate solubility predictions even in cases of extreme melting point values.Citation56Citation58

An additional constraint for early solubility classification is the maximal allowed dose, as it can only be assessed in later R&D stages. A plot of the dependency of the dose number on solubility and the maximal dose () revealed that in the common dose range found for drugs (0.005–1,000 mg), any solubility value above 10 mg/mL would indicate a dose number ≤1. Hence drugs that were estimated as very soluble, freely soluble, soluble or slightly soluble can be provisionally assigned as high-solubility compounds. For drugs with lower solubility estimations, a theoretical dosage range can be used for solubility classification, as was previously shown.Citation12,Citation52

Provisional BCS classification

The provisional BCS classifications with the different in-silico approaches for 185 drugs produced comparable results; on average, 20.76% (±3.07%) of drugs were classified as Class 1, 41.51% (±3.32%) as Class 2, 30.49% (±4.47%) as Class 3, and 6.27% (±4.39%) as Class 4 (). The variability between the different methods in assigning drugs to Class 4 was markedly higher than in the other classes (% coefficient of variation [CV] of 70% versus 7%–15%, respectively). The relatively small sample of Class 4 drugs in our dataset prevents us from conclusively determining the reason. However, our analysis of the distribution of physicochemical properties () may provide some insights: Class 4 drugs had a low and narrow range of partition coefficient values () with significantly higher ranges of melting points () and maximal doses () compared to the other drug classes. These results indicate that BCS Class 4 assignments are the product of several unfavorable traits: a medium–low octanol/water partition ratio, a high melting point, and a high maximal dose. The difficulty to accurately estimate those traits in the earlier R&D stages may account for the poor prediction of Class 4 drugs.

It should be noted that the dataset was compiled exclusively from marketed drugs, and hence does not include compounds at different R&D stages. This could cause an overrepresentation of Class 1, which has favorable developability potential, while the more challenging classes of drugs may be underrepresented, potentially increasing the risk of false positive predictions.

BCS and BDDCS

In 2005 Wu and Benet developed the BDDCS as a complementary system to the BCS.Citation59 The BDDCS classifies drugs according to their fraction dose metabolized rather than their intestinal permeability. It was suggested that these two classification systems are closely linked: the permeation of drugs across cellular membranes makes them readily available for biotransformation by metabolic enzymes; therefore, extensively-metabolized drugs are considered to be highly permeable, and drugs that are mainly excreted unchanged in the urine are low permeability compounds. While the BCS low/high permeability benchmark was set by the FDA as the permeability value of metoprolol, the poor/extensive metabolism benchmark varied from 50% to 70% or 90% over the years.Citation52,Citation60

In a recent publication, Benet noted that passive transcellular permeability is the main predictor of the fraction of drug metabolized.Citation61 Therefore, provisional BCS classifications that are based on LogP calculations are expected to be well-correlated with BDDCS-based classifications. Takagi et al revealed an excellent correlation between their BCS classification of 168 drugs and the respective BDDCS classification for Classes 2 and 4, but lower correlation for Classes 1 and 3.Citation55 Our work is in corroboration with this trend; the provisional in-silico BCS classification underestimated the number of Class 1 drugs while overestimating the number of Class 3 drugs on the database when compared to BDDCS. This trend may be attributed to the lower cutoff point used by Benet for metabolism (70%) compared to the overly conservative permeability marker used in our work (metoprolol).Citation1,Citation38,Citation53 Indeed, when other, lower permeability cutoff standards were selected by Takagi et al the correlation between BDDCS and BCS was significantly enhanced.Citation55

In development of NMEs, the BDDCS has important implications within such areas as brain distribution, enzyme/transporter interplay, and drug–drug interactions.Citation60,Citation61 While metabolism-based classification may misclassify drugs that are excreted unchanged into urine and bile but are highly absorbed (eg, amoxicillin, chloroquine, lomefloxacin, sotalol, trimethoprim, and zalcitabine), classification based merely on LogP calculations may be unable to predict drug transport when active influx/efflux processes are involved. For this reason, the BCS and BDDCS should be regarded as complementary rather than competing approaches.

Conclusion

This work demonstrates that in-silico calculations of physicochemical properties can be used in reliable estimations of solubility and permeability, and in early BCS classification. This classification can be derived from the most basic molecular data; the types of elements and their repetitions in the molecule; the average melting point; and estimations of the dosage range. Thus, drug candidates can be provisionally classified at the very earliest stages of development.

Purely in-silico-based BCS classification may be extremely useful throughout the R&D process: at the earliest stages of drug development, BCS classification would allow selection or engineering of candidate molecules with favorable biopharmaceutical properties for further development.Citation2,Citation11Citation14 Once a candidate molecule is selected and provisionally classified, appropriate polymorph and salt form can be selected, especially for a low solubility drug.Citation16,Citation62 Formulators can then use the provisional BCS classification to plan a strategy to improve its intestinal absorption; if the candidate molecule is classified as low solubility, it may benefit from formulation methods using nanoparticles,Citation63,Citation64 co-solvents,Citation17,Citation65,Citation66 lipid-based formulations,Citation67Citation70 cyclodextrin complexes,Citation18,Citation71Citation73 and other techniques. Low permeability of candidate molecules may be overcome by absorption enhancers.Citation11,Citation25,Citation74,Citation75 However, their unspecific nature may increase the absorption of toxins and other undesirable molecules, thus this approach is often ruled out for safety reasons.Citation2,Citation76 Targeting low permeability molecules to active influx transporters such as Pept 1 may be a more effective strategy for improving their absorption, as was demonstrated for several antiviral prodrugs.Citation47,Citation77,Citation78 Class 4 compounds are extremely challenging to develop, and would require both solubility and permeability improvement approaches.

Lastly, BCS classification could be helpful in assessing the relevance of food–drug interactions. Taking the drug postprandial may delay the absorption of Class 1 drugs, since the rate-limiting step of intestinal absorption for these drugs is gastric emptying. Food intake promotes bile and pancreatic secretions that enable the solubilization and dissolution of low solubility (Class 2 and 4) compounds, and the enhanced viscosity of the gut content may prolong the dissolution and disintegration time of Class 3 drug products.Citation79 Food intake also increases gastric pH, resulting in enhanced or decreased dissolution of acidic or basic drugs, respectively.Citation2,Citation11,Citation80

In conclusion, simplified in-silico estimations of LogP, together with an average melting point and estimated dosage range, can be used for early provisional BCS classification of drugs from their molecular formula. This will allow selection/engineering of candidate molecules with favorable properties; selection of their appropriate polymorphic forms and salts; definition/optimization of their formulation needs; and detection of potential food–drug interactions. The expected overall effect of early BCS classification is enhanced success rates, reduced costs, and accelerated development process of oral drug products.

Disclosure

The authors have no conflicts of interest in this work.

References

  • Dahan A Lennernäs H Amidon GL The fraction dose absorbed, in humans, and high jejunal human permeability relationship Mol Pharm 2012 9 6 1847 1851 22524707
  • Lennernäs H Abrahamsson B The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension J Pharm Pharmacol 2005 57 3 273 285 15807982
  • Amidon GL Lennernäs H Shah VP Crison JR A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 1995 12 3 413 420 7617530
  • Amidon KS Langguth P Lennernäs H Yu LX Amidon GL Bioequivalence of oral products and the biopharmaceutics classification system: science, regulation, and public policy Clin Pharmacol Ther 2011 90 3 467 470 21775984
  • Dahan A Miller JM Amidon GL Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs AAPS J 2009 11 4 740 746 19876745
  • Löbenberg R Amidon GL Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards Eur J Pharm Biopharm 2000 50 1 3 12 10840189
  • Martinez MN Amidon GL A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals J Clin Pharmacol 2002 42 6 620 643 12043951
  • Center for Drug Evaluation and Research, US Food and Drug Administration Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Rockville (MD) FDA 2000
  • Yu LX Amidon G Polli J Biopharmaceutics classification system: the scientific basis for biowaiver extensions Pharm Res 2002 19 7 921 925 12180542
  • Cook J Addicks W Wu Y Application of the biopharmaceutical classification system in clinical drug development–an industrial view AAPS J 2008 10 2 306 310 18500563
  • Ku MS Use of the biopharmaceutical classification system in early drug development AAPS J 2008 10 1 208 212 18446521
  • Pham–The H Garrigues T Bermejo M González–Álvarez I Monteagudo MC Cabrera–Pérez MÁ Provisional classification and in silico study of biopharmaceutical system based on caco-2 cell permeability and dose number Mol Pharm 2013 10 6 2445 2461 23675957
  • Dahan A Wolk O Kim YH Purely in silico BCS classification: science based quality standards for the world’s drugs Mol Pharm 2013 10 11 4378 4390 24094040
  • Lennernäs H Aarons L Augustijns P Oral biopharmaceutics tools – time for a new initiative – an introduction to the IMI project OrBiTo Eur J Pharm Sci 2014 16 57 292 299 24189462
  • Fairstein M Swissa R Dahan A Regional-dependent intestinal permeability and BCS classification: elucidation of pH-related complexity in rats using pseudoephedrine AAPS J 2013 15 2 589 597 23440549
  • Miller JM Beig A Carr RA Spence JK Dahan A A win–win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability Mol Pharm 2012 9 7 2009 2016 22632106
  • Miller JM Beig A Carr RA Webster GK Dahan A The solubility–permeability interplay when using cosolvents for solubilization: revising the way we use solubility-enabling formulations Mol Pharm 2012 9 3 581 590 22280478
  • Miller JM Dahan A Predicting the solubility–permeability interplay when using cyclodextrins in solubility-enabling formulations: model validation Int J Pharm 2012 430 1–2 388 391 22465550
  • Lennernäs H Human intestinal permeability J Pharm Sci 1998 87 4 403 410 9548891
  • Lennernäs H Regional intestinal drug permeation: biopharmaceutics and drug development Eur J Pharm Sci 2014 16 57 333 341 23988845
  • Lennernäs H Human in vivo regional intestinal permeability: importance for pharmaceutical drug development Mol Pharm 2014 11 1 12 23 24206063
  • Dahan A Amidon GL MRP2 mediated drug–drug interaction: indomethacin increases sulfasalazine absorption in the small intestine, potentially decreasing its colonic targeting Int J Pharm 2010 386 1–2 216 220 19944137
  • Dahan A Sabit H Amidon GL The H2 receptor antagonist nizatidine is a P-glycoprotein substrate: characterization of its intestinal epithelial cell efflux transport AAPS J 2009 11 2 205 213 19319690
  • Dahan A Sabit H Amidon GL Multiple efflux pumps are involved in the transepithelial transport of colchicine: combined effect of P-glycoprotein and multidrug resistance-associated protein 2 leads to decreased intestinal absorption throughout the entire small intestine Drug Metab Dispos 2009 37 10 2028 2036 19589874
  • Miller JM Dahan A Gupta D Varghese S Amidon GL Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir Mol Pharm 2010 7 4 1223 1234 20536260
  • Lipinski CA Drug-like properties and the causes of poor solubility and poor permeability J Pharmacol Toxicol Methods 2000 44 1 235 249 11274893
  • Lipinski CA Lombardo F Dominy BW Feeney PJ Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv Drug Deliv Rev 2001 46 1–3 3 26 11259830
  • Winiwarter S Ax F Lennernäs H Hallberg A Pettersson C Karlén A Hydrogen bonding descriptors in the prediction of human in vivo intestinal permeability J Mol Graph Model 2003 21 4 273 287 12479927
  • Benet LZ Broccatelli F Oprea TI BDDCS applied to over 900 drugs AAPS J 2011 13 4 519 547 21818695
  • Hansch C Leo AJ Substituent Constants for Correlation Analysis in Chemistry and Biology New York Wiley 1979
  • Leo AJ Calculating log Poct from structures Chemical Reviews 1993 93 4 1281 1306
  • O’Neil MJ The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals 13th ed Rahway (NJ) Merck 2001
  • Ghose AK Crippen GM Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions J Chem Inf Comput Sci 1987 27 1 21 35 3558506
  • Wildman SA Crippen GM Prediction of physicochemical parameters by atomic contributions J Chem Inf Comput Sci 1999 39 5 868 873
  • Lennernäs H Intestinal permeability and its relevance for absorption and elimination Xenobiotica 2007 37 10–11 1015 1051 17968735
  • Dahan A Miller JM Hilfinger JM High-permeability criterion for BCS classification: segmental/pH dependent permeability considerations Mol Pharm 2010 7 5 1827 1834 20701326
  • Regardh CG Borg KO Johansson R Johnsson G Palmer L Pharmacokinetic studies on the selective beta1-receptor antagonist metoprolol in man J Pharmacokinet Biopharm 1974 2 4 347 364 4155762
  • Zur M Gasparini M Wolk O Amidon GL Dahan A The low/high BCS permeability class boundary: physicochemical comparison of metoprolol and labetalol Mol Pharm 2014 11 5 1707 1714 24735251
  • Klasco RK USP DI® Drug Information for the Health Care Professional Greenwood Village (CO) Thomson Micromedex 2004
  • Amidon GL Williams NA A solubility equation for non-electrolytes in water International Journal of Pharmaceutics 1982 11 3 249 256
  • Chu XY Bleasby K Yabut J Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein J Pharmacol Exp Ther 2007 321 2 673 683 17314201
  • Ganapathy ME Brandsch M Prasad PD Ganapathy V Leibach FH Differential recognition of beta-lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2 J Biol Chem 1995 270 43 25672 25677 7592745
  • Han HK Rhie JK Oh DM CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs J Pharm Sci 1999 88 3 347 350 10052994
  • Kanai Y Endou H Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity J Toxicol Sci 2003 28 1 1 17 12696180
  • Friedman DI Amidon GL Oral absorption of peptides: influence of pH and inhibitors on the intestinal hydrolysis of leu-enkephalin and analogues Pharm Res 1991 8 1 93 96 2014216
  • Amidon GL Chang M Fleisher D Allen R Intestinal absorption of amino acid derivatives: importance of the free alpha-amino group J Pharm Sci 1982 71 10 1138 1141 7143212
  • Dahan A Khamis M Agbaria R Karaman R Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach Expert Opin Drug Deliv 2012 9 8 1001 1013 22703376
  • Yang B Hu Y Smith DE Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice Drug Metab Dispos 2013 41 10 1867 1874 23924683
  • Yang B Smith DE Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice Drug Metab Dispos 2013 41 3 608 614 23264448
  • Soldner A Benet LZ Mutschler E Christians U Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers Br J Pharmacol 2000 129 6 1235 1243 10725273
  • Weiss J Sauer A Divac N Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters Biopharm Drug Dispos 2010 31 2–3 150 161 20222053
  • Broccatelli F Cruciani G Benet LZ Oprea TI BDDCS class prediction for new molecular entities Mol Pharm 2012 9 3 570 580 22224483
  • Incecayir T Tsume Y Amidon GL Comparison of the permeability of metoprolol and labetalol in rat, mouse, and Caco-2 cells: use as a reference standard for BCS classification Mol Pharm 2013 10 3 958 966 23327720
  • Kasim NA Whitehouse M Ramachandran C Molecular properties of WHO essential drugs and provisional biopharmaceutical classification Mol Pharm 2004 1 1 85 96 15832504
  • Takagi T Ramachandran C Bermejo M Yamashita S Yu LX Amidon GL A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan Mol Pharm 2006 3 6 631 643 17140251
  • Bergström CAS Norinder U Luthman K Artursson P Molecular descriptors influencing melting point and their role in classification of solid drugs J Chem Inf Comput Sci 2003 43 4 1177 1185 12870909
  • Preiss U Bulut S Krossing I In silico prediction of the melting points of ionic liquids from thermodynamic considerations: a case study on 67 salts with a melting point range of 337 degrees C J Phys Chem B 2010 114 34 11133 11140 20690695
  • Zhang Y Maginn EJ A comparison of methods for melting point calculation using molecular dynamics simulations J Chem Phys 2012 136 14 144116 22502510
  • Wu CY Benet LZ Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system Pharm Res 2005 22 1 11 23 15771225
  • Custodio JM Wu CY Benet LZ Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 2008 60 6 717 733 18199522
  • Benet LZ The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development J Pharm Sci 2013 102 1 34 42 23147500
  • Dahan A Beig A Ioffe–Dahan V Agbaria R Miller J The twofold advantage of the amorphous form as an oral drug delivery practice for lipophilic compounds: increased apparent solubility and drug flux through the intestinal membrane AAPS J 2013 15 2 347 353 23242514
  • Dahan A Miller JM The solubility-permeability interplay and its implications in formulation design and development for poorly soluble drugs AAPS J 2012 14 2 244 251 22391790
  • Morgen M Bloom C Beyerinck R Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug Pharm Res 2012 29 2 427 440 21863477
  • Beig A Miller JM Dahan A Accounting for the solubility–permeability interplay in oral formulation development for poor water solubility drugs: the effect of PEG-400 on carbamazepine absorption Eur J Pharm Biopharm 2012 81 2 386 391 22387337
  • Miller JM Beig A Krieg BJ The solubility–permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation Mol Pharm 2011 8 5 1848 1856 21800883
  • Dahan A Hoffman A Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: Correlation with in vivo data and the relationship to intra-enterocyte processes in rats Pharm Res 2006 23 9 2165 2174 16902814
  • Dahan A Hoffman A The effect of different lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats Eur J Pharm Biopharm 2007 67 1 96 105 17329087
  • Dahan A Hoffman A Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs J Control Release 2008 129 1 1 10 18499294
  • Koga K Takarada N Takada K Nano-sized water-in-oil-in-water emulsion enhances intestinal absorption of calcein, a high solubility and low permeability compound Eur J Pharm Biopharm 2010 74 2 223 232 19755156
  • Beig A Agbaria R Dahan A Oral delivery of lipophilic drugs: the tradeoff between solubility increase and permeability decrease when using cyclodextrin-based formulations PLoS One 2013 8 7 e68237 23874557
  • Beig A Miller JM Dahan A The interaction of nifedipine with selected cyclodextrins and the subsequent solubility-permeability trade-off Eur J Pharm Biopharm 2013 85 3 1293 1299 23770429
  • Dahan A Miller JM Hoffman A Amidon GE Amidon GL The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: mechanistic modeling and application to progesterone J Pharm Sci 2010 99 6 2739 2749 20039391
  • Miller JM Dahan A Gupta D Varghese S Amidon GL Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs J Control Release 2009 137 1 31 37 19264104
  • Sharma P Varma MV Chawla HP Panchagnula R In situ and in vivo efficacy of peroral absorption enhancers in rats and correlation to in vitro mechanistic studies Farmaco 2005 60 11–12 874 883 16243320
  • Sun J Dahan A Amidon GL Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach J Med Chem 2010 53 2 624 632 19957998
  • Gupta D Varghese Gupta S Dahan A Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue Mol Pharm 2013 10 2 512 522 23244438
  • Varghese Gupta S Gupta D Sun J Enhancing the intestinal membrane permeability of zanamivir: a carrier mediated prodrug approach Mol Pharm 2011 8 6 2358 2367 21905667
  • Radwan A Amidon GL Langguth P Mechanistic investigation of food effect on disintegration and dissolution of BCS class III compound solid formulations: the importance of viscosity Biopharm Drug Dispos 2012 33 7 403 416 22782559
  • Dahan A Duvdevani R Shapiro I Elmann A Finkelstein E Hoffman A The oral absorption of phospholipid prodrugs: in vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration J Control Release 2008 126 1 1 9 18082281