A novel simulated media system for in vitro evaluation of bioequivalent intestinal drug solubility.

Orally administered solid drug must dissolve in the gastrointestinal tract before absorption to provide a systemic response. Intestinal solubility is therefore crucial but difficult to measure since human intestinal fluid (HIF) is challenging to obtain, varies between fasted (Fa) and fed (Fe) states and exhibits inter and intra subject variability. A single simulated intestinal fluid (SIF) cannot reflect HIF variability, therefore current approaches are not optimal. In this study we have compared literature Fa/FeHIF drug solubilities to values measured in a novel in vitro simulated nine media system for either the fasted (Fa9SIF) or fed (Fe9SIF) state. The manuscript contains 129 literature sampled human intestinal fluid equilibrium solubility values and 387 simulated intestinal fluid equilibrium solubility values. Statistical comparison does not detect a difference (Fa/Fe9SIF vs Fa/FeHIF), a novel solubility correlation window enclosed 95% of an additional literature Fa/FeHIF data set and solubility behaviour is consistent with previous physicochemical studies. The Fa/Fe9SIF system therefore represents a novel in vitro methodology for bioequivalent intestinal solubility determination. Combined with intestinal permeability this provides an improved, population based, biopharmaceutical assessment that guides formulation development and indicates the presence of food based solubility effects. This transforms predictive ability during drug discovery and development and may represent a methodology applicable to other multicomponent fluids where no single component is responsible for performance.

Imiquimod Solubility in Different Solvents: An Interpretative Approach.

Imiquimod (IMQ) has been successfully formulated to date mainly as semi-solid lipophilic formulations for topical application. In this study, we investigated the solubility of IMQ in solvents suitable for developing innovative formulations in the form of powder obtained, for instance, by spray drying; thus, water, ethanol, methanol, acetone, acetonitrile, and dimethyl sulfoxide were tested at different temperatures. Temperature variations, stirring intensity, and the contact time between IMQ and the solvent greatly affected the evaluation of IMQ equilibrium solubility. The attainment of the solid-liquid equilibrium requires 13 days starting from solid IMQ and 2 days from a cooled-down supersaturated IMQ solution. A correlation between IMQ solubility and the solubility parameters of solvents was not found. IMQ solutions in water, ethanol, methanol, acetonitrile, and dimethyl sulfoxide were neither ideal nor regular. The Scatchard-Hildebrand equation does not apply to IMQ solutions because of association phenomena due to intermolecular hydrogen bonds and/or π-stacking, as supported by the hyperchromic effect that was very pronounced in highly polar solvents, such as water, with the increase in temperature. Finally, IMQ solubility values measured in acetone cannot be considered reliable due to the reaction with the solvent, leading to the formation of new molecules.

Excipient Impact on Fenofibrate Equilibrium Solubility in Fasted and Fed Simulated Intestinal Fluids Assessed Using a Design of Experiment Protocol.

Solubility is a critical parameter controlling drug absorption after oral administration. For poorly soluble drugs, solubility is influenced by the complex composition of intestinal media and the influence of dosage form excipients, which can cause bioavailability and bioequivalence issues. This study has applied a small scale design of experiment (DoE) equilibrium solubility approach in order to investigate the impact of excipients on fenofibrate solubility in simulated fasted and fed intestinal media. Seven media parameters (bile salt (BS), phospholipid (PL), fatty acid, monoglyceride, cholesterol, pH and BS/PL ratio) were assessed in the DoE and in excipient-free media, and only pH and sodium oleate in the fasted state had a significant impact on fenofibrate solubility. The impact of excipients were studied at two concentrations, and for polyvinylpyrrolidone (PVP, K12 and K29/32) and hydroxypropylmethylcellulose (HPMC, E3 and E50), two grades were studied. Mannitol had no solubility impact in any of the DoE media. PVP significantly increased solubility in a media-, grade- and concentration-dependent manner, with the biggest change in fasted media. HPMC and chitosan significantly reduced solubility in both fasted and fed states in a media-, grade- and concentration-dependent manner. The results indicate that the impact of excipients on fenofibrate solubility is a complex interplay of media composition in combination with their physicochemical properties and concentration. The results indicate that in vitro solubility studies combining the drug of interest, proposed excipients along with suitable simulated intestinal media recipes will provide interesting information with the potential to guide formulation development.

A Novel Betulinic Acid Analogue: Synthesis, Solubility, Antitumor Activity and Pharmacokinetic Study in Rats.

Betulinic acid (BA) and betulin (BE) are naturally pentacyclic triterpenes with documented biological activities, especially antitumor and anti-inflammatory activity. However, their bioavailability in vivo is not satisfactory in terms of medical applications. Thus, to improve the solubility and bioavailability so as to improve the efficacy, 28-O-succinyl betulin (SBE), a succinyl derivative of BE, was synthesized and its solubility, in vitro and in vivo anti-tumor activities, the apoptosis pathway as well as the pharmacokinetic properties were investigated. The results showed that SBE exhibited significantly higher solubility in most of the tested solvents, and showed a maximum solubility of 7.19 ± 0.66 g/L in n-butanol. In vitro and in vivo anti-tumor activity assays indicated both BA and SBE exhibited good anti-tumor activities, and SBE demonstrated better potential compared to BA. An increase in the ratio of Bad/Bcl-xL and activation of caspase 9 was found in SBE treated Hela cells, suggesting that the intrinsic mitochondrial pathway is involved in SBE induced apoptosis. Compared with BA, SBE showed much-improved absorption and bioavailability in pharmacokinetic studies.

Phosphate buffer interferes dissolution of prazosin hydrochloride in compendial dissolution testing.

The purpose of this study was to elucidate the lack of supersaturation behavior in the dissolution profile of prazosin hydrochloride (PRZ-HCl) in the compendial dissolution test. The equilibrium solubility was measured by a shake-flask method. Dissolution tests were performed by a compendial paddle method with a phosphate buffer solution (pH 6.8, 50 mM phosphate). The solid form of the residual particles was identified by Raman spectroscopy. In the pH range below 6.5, the equilibrium solubility in phosphate buffer was lower than that in the unbuffered solutions (pH adjusted by HCl and NaOH). Raman spectra showed that the residual solid was a phosphate salt of PRZ. In the pH range above 6.5, the pH-solubility profiles in the phosphate buffer solutions and the unbuffered solutions were the same. The residual solid was a PRZ freebase (PRZ-FB). In the dissolution test, PRZ-HCl particles first changed to a phosphate salt within 5 min, then gradually changed to PRZ-FB after several hours. Since the intestinal fluid is buffered by the bicarbonate system in vivo, the dissolution behavior in vivo may not be properly evaluated using a phosphate buffer solution. For drugs with a low phosphate solubility product, it is necessary to consider this aspect.

Donepezil Hydrochloride BCS Class Ambiguity: Relevant Aspects to be Considered in Drug Classification.

Donepezil hydrochloride (DH) is the most used anti-Alzheimer's disease drug, however, its classification according to the Biopharmaceutics Classification System (BCS) is not clear in the literature. BCS is one of the accepted criteria used to grant biowaiver (waiver of in vivo bioequivalence studies) of new drug products. So, the purpose of this work was to elucidate the BCS classification of DH and to raise the discussion about the possibility of biowaiver for new medicines containing it. The polymorphic form was previously identified as form III of DH. The drug showed high solubility in the entire pH range evaluated (1.2 to 6.8, at 37 °C) with a pH-dependent solubility profile. The effective permeability (Peff) values obtained with different DH concentrations, using in situ closed-loop perfusion model were statistically similar (p > 0.05), even when compared to high permeability control used (ketoprofen), demonstrating that DH has high permeability which, associated with its high solubility, allows to classify DH as BCS class 1. Relevant data to evaluate for granting a biowaiver for new medicines were also reviewed from the literature. Based on information reunited new immediate-release drug products containing DH should be eligible for BCS-based biowaiver.

Structure-property relations of a unique and systematic dataset of 19 isostructural multicomponent apremilast forms.

The structure-property relations are examined for apremilast cocrystals and solvates in this work. A unique and large dataset of multicomponent crystal forms is presented including 7 cocrystals and 12 solvates. In total, 15 of the presented multicomponent forms and their crystal structures are published here for the first time. This dataset is unique owing to the extreme crystal packing similarity of all 19 crystal forms. This fact makes the evaluation of structure-property relations significantly easier and more precise since the differences in the crystal lattice arrangement are close to negligible. Properties of the guest molecules used here can be directly correlated with the macroscopic properties of the corresponding multicomponent forms. Interestingly, a considerable correlation was found between the intrinsic dissolution rate of the multicomponent forms and their solubility, as well as the solubility of their guest molecules in the dissolution medium. The latter is of particular interest as it can aid in the design of multicomponent forms with tuned properties.

Biopharmaceutical evaluation of kavain in Piper methysticum G. Forst dried extract: Equilibrium solubility and intestinal permeability in Caco-2 cell model.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper methysticum G. Forst, popularly known as kava, is a traditional medicinal plant native from South Pacific islands and widely used to treat anxiety, depression and stress. The psychoactive properties are related to the kavalactones, mainly kavain. AIM OF THE STUDY: To evaluate the biopharmaceutical properties of synthetic kavain and when present in kava dried extracts by means of equilibrium solubility and intestinal permeability studies in the Caco-2 cell model. MATERIALS AND METHODS: The equilibrium solubility of kavain was performed using a shake flask incubator at 37 °C in different media at physiological pH range (1.2-6.8). The intestinal permeability of kavain evaluated in Caco-2 cells in the presence and absence of the P-glycoprotein inhibitor verapamil. Kavain concentrations were determined by reversed phase high performance liquid chromatography (HPLC). RESULTS: HPLC methods were developed and fully validated for kavain quantitation. Kavain demonstrated low solubility and the pH of the aqueous media did not affect its solubility. Kavain was found to be highly permeable and efflux of kavain mediated by P-glycoprotein was not significant during intestinal permeation. CONCLUSION: The results of biopharmaceutical studies provided useful information for predicting availability of kavain from the gastrointestinal tract and this compound was ranked as BCS Class II, exhibiting dissolution rate-limited absorption.

Tuning Potency of Bioactive Molecules via Polymorphic Modifications: A Case Study.

Polymorphism in drugs and bioactive molecules is not uncommon, and it has remained as one of the critical issues in drug development processes. While improving physicochemical properties of bioactive molecules has been a prime focus of the pharmaceutical chemists, not much efforts have been put toward the improvement of their potency via polymorphic modifications. Here, we consider five cases of 5-arylidene-2-aminothiazolidinones derivatives, the known anticancer agents, and discover eights polymorphs in three out of the five cases. We perform systematic crystallization experiments and detailed crystal structure analysis of the eight polymorphs and two compounds, estimate both their energetic and thermal stabilities, and compare their solid state properties. We also compare in-solution properties, e.g., equilibrium solubility, intrinsic dissolution rate, and phase stability, of three polymorphs of one of the cases. Further, we study the extent of inhibition imposed by those eight polymorphs and seven bulk and crystal forms of the compounds on the proliferation of MCF7 breast cancer cells and also the extent of their binding to the isozyme γ-enolase. Furthermore, we perform MD simulations on the eight polymorphs and one compound to estimate and compare their binding affinity with γ-enolase. Our experimental and MD simulation analyses in general emphasize the importance of polymorphism in improving the biological potency of individual molecules.

Exploring Taxifolin Polymorphs: Insights on Hydrate and Anhydrous Forms.

Taxifolin, also known as dihydroquercetin, possesses several interesting biological properties. The purpose of the study was to identify polymorphs of taxifolin prepared using crystallization in different solvents. Data from X-ray powder diffraction, differential scanning calorimetry, and thermogravimetry enabled us to detect six different crystalline phases for taxifolin. Besides the already known fully hydrated phase, one partially hydrated phase, one monohydrated phase, two anhydrous polymorphs, and one probably solvated phase were obtained. The unit cell parameters were defined for three of them, while one anhydrous polymorph was fully structurally characterized by X-ray powder diffraction data. Scanning electron microscopy and hot stage microscopy were also employed to characterize the crystallized taxifolin powders. The hydrate and anhydrous forms showed remarkable stability in drastic storage conditions, and their solubility was deeply evaluated. The anhydrous form converted into the hydrate form during the equilibrium solubility study and taxifolin equilibrium solubility was about 1.2 mg/mL. The hydrate taxifolin intrinsic dissolution rate was 56.4 µg cm-2 min-1. Using Wood's apparatus, it was not possible to determine the intrinsic dissolution rate of anhydrous taxifolin that is expected to solubilize more rapidly than the hydrate form. In view of its high stability, its use can be hypothesized.

Cellulose derivatives as effective recrystallization inhibitor for ternary ritonavir solid dispersions: In vitro-in vivo evaluation.

Amorphous solid dispersions (ASDs) are regarded as one of the most promising techniques for poorly-soluble active pharmaceutical ingredients (API). However, the thermodynamic instability of ASDs at supersaturated state makes them easy to recrystallize in aqueous media. In this study, ritonavir (RTV) was selected as a model drug for evaluating the solubility enhancement and recrystallization inhibition effect of various cellulose derivatives and the combinations of them with typical surfactants. Combination of HPMCAS-HF/SLS was filtrated for preparing ternary RTV solid dispersions (RTV SD) via solvent evaporation method. RTV SD exhibited enhanced dissolution manner, while the oral bioavailability of RTV SD was equivalent with the Reference Standard Norvir® but increased significantly compared to the ternary physical mixture. Thus, the ternary SD system might be promisingly employed as efficient drug delivery system for RTV, while the HPMCAS-HF/SLS combination could be recommended as effective excipient for fabricating steady solid dispersions loading poorly soluble API.

Stable solid dispersion of lurasidone hydrochloride with augmented physicochemical properties for the treatment of schizophrenia and bipolar disorder.

Crystalline solid dispersion of lurasidone hydrochloride (LH) was made with various polar and non-polar small molecules to overcome the poor aqueous solubility issue. LH-Glutathione (GSH) solid dispersion in 1:1 ratio was prepared by co-grinding method and characterized by using differential scanning calorimetry (DSC), powder X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. GSH acts as antioxidant and reported for anti-schizophrenic activity may provide synergistic action with LH or reduce the side effects. LH in LH-GSH solid dispersion (SD) has shown improvement in solubility by 7.9 folds than plain drug which translated in terms of improved dissolution rate by two-folds. The in vitro dissolution results showed maximum dissolution rate with LH-GSH SD (97.85 ± 2.40%) compared to plain drug (50.5 ± 3.02%) at 15 min (t15 min, %) and thus, satisfying criteria of immediate release dosage form. DSC and FTIR data confirmed the stability of LH-GSH SD for 3 months at accelerated stability condition (40 ± 2°C and 75 ± 5% RH). The prepared LH-GSH SD can be used as a tool to target dual problems that is, enhanced physicochemical properties along with possible management of disorder which could be due to synergism with co-administered GSH. This approach is thought to be efficiently providing the relief to the psychological patients.

Development of binary dispersions and nanocomposites of irbesartan with enhanced antihypertensive activity.

Introduction: Irbesartan (IBS), an angiotensin II receptor (AT1 subtype) antagonist which blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective binding to AT1 angiotensin II receptor. It belongs to BCS class II drug (low aqueous solubility and high permeability). Improvement of dissolution characteristics of the drug by formulating is being investigated in the current study. Methods: Solid dispersions (SD) formulations were prepared by the melting fusion technique and nanocomposites (NC) were prepared by a single emulsion technique. Eight batches of SD and three batches of NC were formulated in three ratios of drug to polymer (1:1, 1:2, and 1:3). The batches were evaluated for equilibrium solubility studies, Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), field emission SEM (FESEM), transmission electron microscopy (TEM), and in vitro dissolution studies. Results: Solubility studies revealed maximum solubility at a 1:2 ratio of solid dispersions and a 1:1 ratio of nanocomposites. No drug-polymer interaction was observed in FTIR results. DSC, SEM, and XRD analysis revealed changes in drug crystallinity i.e. conversion to the amorphous state of drugs. Nanosize of particles in the NC1 batch was confirmed in TEM studies. Solid dispersions and nanocomposites showed significant enhancement of dissolution in comparison to that of the pure drug (100% drug release in approximately 1 hour). Conclusion: Nanocomposites proved superior carriers to solid dispersions in terms of the dissolution enhancement. Further, in vivo studies indicated that the induction of systolic and diastolic blood pressure in the optimized formulation (NC1) was significantly decreased in comparison to the disease control group (P <0.01) at all time intervals along with pure drug (P <0.05).

Buclizine crystal forms: First Structural Determinations, counter-ion stoichiometry, hydration, and physicochemical properties of pharmaceutical relevance.

Buclizine (BCZ) is a chiral synthetic piperazine derivative which has antihistaminic, anti-muscarinic and antiemetic properties, and has been reintroduced as an appetite stimulant, especially for pediatric patients. Structural information about this drug, as well as other buclizine crystalline forms (solvates, salts and co-crystals) including the BCZ free-base (BCZ-FB), is non-existent. Here, we present for the first time the crystal structure of the monohydrochloride monohydrate salt of BCZ (BCZHCl·H2O), and of its anhydrous form, BCZHCl. Interestingly, BCZHCl·H2O was obtained by recrystallization from the raw material (BCZH2Cl2) in ethanol:water solution showing that BCZ anhydrous dihydrochloride salt changes easily to a monohydrochloride monohydrate salt modification, which raise concerns about formulation quality control. BCZHCl·H2O and BCZHCl crystallize in the orthorhombic space groups (Pna21 and Pca21) belonging to the mm2 point group and are thus classified as non-centrosymmetric achiral structures (NA). Intuitively, we expect these salts to crystallize in a space group with a center of symmetry, since less than 5% of the known racemic compounds crystallize in the NA type. The crystal structures of BCZH2Cl2 and BCZ-FB were not determined, but their existence was verified by other techniques (chloride ion analysis, PXRD, HPLC, FT-IR, DSC, TGA) and by comparison of the obtained results with those found for BCZHCl. Additionally, we have also performed an evaluation of the equilibrium solubility (at six different aqueous media) and the dissolution profile of the BCZHCl salt compared to the raw material and BCZ-FB. Different equilibrium solubility values were found comparing the three forms in acidic and neutral pH ranges and all of them were insoluble at pH > 7.0. Moreover, tablets prepared with BCZH2Cl2, BCZHCl or BCZ-FB show significant differences in terms of dissolution profile.

Revisit of solubility of oxytetracycline polymorphs. An old story in the light of new results.

In the literature the therapeutic nonequivalence of oxytetracycline hydrochloride (OTCH) capsules and tablets was attributed to the different aqueous solubility of polymorphs without their comprehensive study. Our aim was to reveal the effects of polymorphism on equilibrium solubility, dissolution kinetics and the supersaturation of two OTCH polymorphs (stable Form A and metastable Form B).The equilibrium solubility was measured in biorelevant pH range 4-7.4 by the standardized saturation shake-flask method. We also studied the solubility in SGF at pH 1.2 and the effect of the pH change from 1.2 to 5.0 on solubility. The dissolution was studied using real-time concentration monitoring with an ATR probe attached to a UV spectrophotometer (µDISS Profiler). A wide spectrum of solid phase analysis methods (SEM, IR, XRPD, Raman) was applied for characterization of polymorphs and to identify which form is present at the equilibrium solubility. Identical equilibrium solubility values were obtained at the same pHs in region 4.0-7.4 using the two polymorphs as starting materials. The XRPD analysis of the isolated solid phases proved that both polymorphic forms were converted to dihydrate form. In situ monitoring of the dissolution at pH 5.0 showed immediate dissolution, no difference in supersaturation, and short equilibration time for both forms indicating the immediate conversion. In SGF (pH 1.2) Form B dissolved better than Form A and showed significantly different dissolution kinetic and stability. A long-lasting, false chain-citation stating that Form B dissolves 28x better in water than Form A, was cut by the present study (i) revealing that the cited data was measured in IPA not in water, and (ii) proving that only the intrinsic solubility of OTC dihydrate can be measured in water due to conversion of polymorphs under the experimental conditions of solubility measurement. However this conversion is inhibited below pH 1.5, so the differences in solubility and dissolution kinetic found at pH 1.2 may contribute to the interpretation of the different serum-levels reported at solid formulations.

A review of methods for solubility determination in biopharmaceutical drug characterization.

The significance of thermodynamic solubility in biopharmaceutical compound or drug characterization as well as the importance of having methods that accurately establish it have been extensively addressed. Nonetheless, its precise determination continues to remain a challenging task to accomplish. Even more so when the number of compounds to evaluate is high and the available amount of each compound is low, both of which are inevitable for the compound characterization during the drug development process. Except for the shake-flask method which is still considered as the 'gold standard' in obtaining thermodynamic data, it is currently difficult to say that another satisfactory model which is routinely used to determine thermodynamic solubility is being applied. Therefore, this review summarizes the various experimental approaches which are based on the classical shake flask method but have yet attempted to speed up the experimental process of obtaining such data more conveniently. The most important experimental features of these approaches are provided to the reader. Some advantages and disadvantages associated with each approach are also highlighted, consequently offering a resource to those looking for the most appropriate of the approaches that have already fared well at determining the biopharmaceutically relevant drug solubility.

Synthesis of budesonide conjugates and their anti-inflammatory effects: a preliminary study.

PURPOSE: Budesonide (Bud) is a nonhalogenated glucocorticoid with high anti-inflammatory potency and low systemic side effects. However, the poor water solubility of Bud affects its dissolution and release behavior, thus influencing its anti-inflammatory effect. This study was aimed at synthesizing and evaluating novel conjugates of Bud, hoping to increase the anti-inflammatory activity of Bud by improving its water solubility. MATERIALS AND METHODS: Seven novel Bud conjugates (3a-3g) were designed and synthesized in this study. Besides, the equilibrium solubility, cell viability, in vitro and in vivo anti-inflammatory activity, and the hydrolysis behavior of the conjugates in different pH solutions, rat and human plasma, and rat lung homogenate were studied in detail. RESULTS: As compared to Bud, the equilibrium solubility of 3a, 3c, and 3e was significantly increased; 3a, 3b, and 3c significantly inhibited the interleukin-6 production in lipopolysaccharide-induced A549 cells; 3a and 3e could significantly decrease the xylene-induced ear edema; and 3a and 3c were gradually and slowly hydrolyzed into Bud in the alveolar fluid and lung homogenate and broken down quickly in plasma. CONCLUSION: The amino acid ester compounds budesonide-21-glycine ester (3a) and budesonide-21-alanine ester (3c) were selected as potential conjugates of Bud. This study would provide a theoretical and an experimental basis for the in vivo process of glucocorticoids and the treatment of inflammatory diseases.

Harmonizing solubility measurement to lower inter-laboratory variance - progress of consortium of biopharmaceutical tools (CoBiTo) in Japan.

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The "mandatory" and "recommended" procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP.

Polymorphic and Quantum Chemistry Characterization of Candesartan Cilexetil: Importance for the Correct Drug Classification According to Biopharmaceutics Classification System.

The recommended method for the biopharmaceutical evaluation of drug solubility is the shake flask; however, there are discrepancies reported about the solubility of certain compounds measured with this method, one of them is candesartan cilexetil. The present work aimed to elucidate the solubility of candesartan cilexetil by associating others assays such as stability determination, polymorphic characterization and in silico calculations of intrinsic solubility, ionized species, and electronic structures using quantum chemistry descriptors (frontier molecular orbitals and Fukui functions). For the complete biopharmaceutical classification, we also reviewed the permeability data available. The polymorphic form used was previously identified as the form I of candesartan cilexetil. The solubility was evaluated in biorelevant media in the pH range of 1.2-6.8 at 37.0°C according to the stability previously assessed. The solubility of candesartan cilexetil is pH dependent and the dose/solubility ratios obtained demonstrated the low solubility of the prodrug. The in silico calculations supported the found results and evidenced the main groups involved in the solvation, benzimidazole, and tetrazol-biphenyl. The human absolute bioavailability reported demonstrates that candesartan cilexetil has low permeability and when associated with the low solubility allows to classify it as class 4 of the Biopharmaceutics Classification System.