Elucidation of Solution State Complexation in Wet-Granulated Oven-Dried Ibuprofen and β-Cyclodextrin: FT-IR and 1H-NMR Studies

The effect of oven-dried wet granulation on the complexation of β-cyclodextrin with ibuprofen (IBU) in solution was investigated using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (¹H NMR), and molecular modeling. Granulation was carried out using 5 mL of three different granulating solvents; water, ethanol (95% v/v), and isopropanol and the granules were oven-dried at 60°C for 2 h. The granules were compared to oven-dried physical mixture and conventionally prepared complex. Phase solubility study was performed to investigate the stability of the granulation-formed complexes in solution. FT-IR was used to examine the complexation in the granules while ¹H NMR, and molecular modeling studies were carried out to determine the mechanism of complexation in the water-prepared granules. The solubility studies suggested a 1:1 complex between IBU and βCD. It also showed that the stability of the complex in solution was in the following order with respect to the granulating solvents: ethanol > water > isopropanol. The FT-IR study revealed a shift in the carboxylic acid stretching band and decrease in the intensities of the C-H bending bands of the isopropyl group and the out-of-plane aromatic ring, of IBU, in granules compared to the oven-dried physical mixture. This indicated that granules might have some extent of solid state complexation that could further enhance dissolution and the IBU–βCD solution state complexation. ¹H NMR showed that water prepared oven-dried granules had a different ¹H NMR spectrum compared to similarly made oven-dried physical mixture, indicative of complexation in the former. The ¹H NMR and the molecular modeling studies together revealed that solution state complexation from the granules occurred by inclusion of the isopropyl group together with part of the aromatic ring of IBU into the βCD cavity probably through its wider side. These results indicate that granulation process induced faster complexation in solution which enhances the solubility and the dissolution rate of poorly soluble drugs. The extent of complexation in the granules was dependent on the type of solvent used.     

Comparative Study on Inclusion Complexation of Maltosyl-β-cyclodextrin,Heptakis(2,6-di-O-methyl)-β-cyclodextrin and β-Cyclodextrin with Fucosterol in Aqueous and Solid State

Abstract— The complexation of fucosterol with three kinds of β-cyclodextrin (β-CyD) was investigated in aqueous solution and in the solid state. The solubility of fucosterol increased significantly on its complexation with maltosyl-β-CyD and heptakis(2,6-di-O-methyl)-β-CyD (DM-β-CyD), while no appreciable increase was observed when complexed with β-CyD. The stability constant of complexation with β-CyD estimated from solubility determinations was greater for a 1:2 complex than for a 1:1 complex. On the other hand, 1:1 complexation of fucosterol with maltosyl-β-CyD or DM-β-CyD was greater than 1:2 complexation. The solid complexes were obtained in molar ratios of 1:2 and 1:3 for β-CyD and maltosyl-β-CyD complexes, respectively. The inclusion behaviour of fucosterol with maltosyl-β-CyD was compared with β-CyD in the solid state using DSC, powder X-ray diffractometry and CP/MAS ¹³C NMR. Maltosyl-β-CyD showed different inclusion behaviour compared with β-CyD, and produced an amorphous structure of fucosterol on complex formation. The dissolution rate of fucosterol-maltosyl-β-CyD complex was significantly faster than other complexes due to its high aqueous solubility and amorphous structure.     

Hydrotropic Solubilization— Mechanistic Studies

Purpose. This study examines the mechanism of hydrotropic solubilization using the riboflavin-nicotinamide system. The most commonly proposed mechanism for hydrotropic solubilization is complexation, and therefore, is investigated. Additionally, since nicotinamide and several other hydrotropic agents self-associate in aqueous solution, the possibility that self-association of the hydrotropic agent is important mechanistically is examined by studying the effect of temperature on hydrotropic ability. Researchers have shown that the degree of self-association decreases with increasing temperature. Therefore, if temperature affects the solubilizing capacity of nicotinamide, self-association must be mechanistically significant. Methods. The complexation hypothesis is tested by looking at nicotinamide's ability to quench riboflavin fluorescence and by examining changes in the UV/Vis spectrum of riboflavin upon addition of nicotinamide. The solubility of riboflavin in nicotinamide solutions as a function of temperature is determined to assess the impact of self-association on hydrotropicity. Results. Nicotinamide does not alter the intrinsic fluorescence of riboflavin nor are changes indicative of complexation observed in the UV/Vis spectrum. Temperature does have an effect on the hydrotropic ability of nicotinamide. Specifically, as temperature increases, the solubilizing capacity of nicotinamide decreases. Conclusions. Because nicotinamide is unable to quench riboflavin fluorescence, and does not produce significant spectral changes, complexation of nicotinamide and riboflavin does not occur. However, since increasing temperature causes a decrease in the hydrotropic ability of nicotinamide and in its degree of self-association, it is proposed here that the self-association of nicotinamide impacts the hydrotropic mechanism.     

Hydrotropic Solubilization of Paclitaxel: Analysis of Chemical Structures for Hydrotropic Property

Purpose. To identify hydrotropic agents that can increase aqueous paclitaxel (PTX) solubility and to study the chemical structures necessary for hydrotropic properties so that polymeric hydrotropic agents can be synthesized. Methods. More than 60 candidate hydrotropic agents (or hydro- tropes) were tested for their ability to increase the aqueous PTX solubility. A number of nicotinamide analogues were synthesized based on the observation that nicotinamide showed a favorable hydrotropic property. The identified hydrotropes for PTX were used to examine the structure-activity relationship.Results. N,N-Diethylnicotinamide (NNDENA) was found to be the most effective hydrotropic agent for PTX. The aqueous PTX solubility was 39 mg/ml and 512 mg/ml at NNDENA concentrations of 3.5 M and 5.95 M, respectively. These values are 5-6 orders of magnitude greater than the intrinsic solubility of 0.30 ± 0.02 g/ml. N-Picolylnicotinamide, N-allylnicotinamide, and sodium salicylate were also excellent hydrotropes for PTX. Solubility data showed that an effective hydrotropic agent should be highly water soluble while maintaining a hydrophobic segment. Conclusions. The present study identified several hydrotropic agents effective for increasing aqueous solubility of PTX and analyzed the structural requirements for this hydrotropic property. This information can be used to find other hydrotropic compounds and to synthesize polymeric hydrotropes that are effective for PTX and other poorly water-soluble drugs.     

Micellar complexes of all-trans retinoic acid with polyvinylalcohol-nicotinoyl esters as new parenteral formulations in neuroblastoma

All-trans-retinoic acid (ATRA) is now included in many antitumor therapeutic schemes for the treatment of acute promyelocytic leukemia, Kaposi’s sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer, and neuroblastoma. Unfortunately, its poor aqueous solubility hampers its parenteral formulation, whereas oral administration of ATRA is associated with progressively diminishing drug levels in plasma, which is related to induction of retinoic acid-binding proteins and increased drug catabolism by cytochrome P450-mediated reactions. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects. To this purpose, amphiphilic polymers were prepared by polyvinylalcohol (PVA) partial esterification with nicotinoyl moieties and their functional properties evaluated with regard to ATRA complexation. The physicochemical characteristics of the polymers and the complexes were analyzed by ¹H-NMR, Dynamic Light Scattering (DLS), Capillary Electophoresis (CE), and were correlated with the complex ability to improve the drug solubilization and release the free drug in an aqueous environment. Subsequently, the best complex, providing the highest ATRA solubilization and release, was evaluated in vitro to test its citotoxicity towards neuroblastoma cell lines. The PVA substitution degree calculated from ¹H-NMR was found to be 5.0%, 8.2%, 15.3% (nicotinoyl moiety:PVA monomer molar ratio), while capillary electrophoresis analysis on the complexes revealed that the drug loadings were 0.95%, 1.20%, 4.76% (ATRA:polymer w:w) for PVA substitution degrees of 5.0%, 8.2%, and 15.3%, respectively. Complexation strongly increased ATRA aqueous solubility, which reached 1.20 ± 0.25 mg/mL. The DLS measurements of the polymers and the complexes in aqueous solutions revealed mean sizes always below 400 nm, low polydispersity (min 0.202 ± 0.013, max 0.450 ± 0.032), and size almost unaffected by concentration. Drug fractional release did not exceed 8% after 48 h. The cytotoxicity studies against neuroblastoma cell lines outlined a significant growth inhibition effect of complexed ATRA with respect to free ATRA. These data suggest that the systems analyzed may be suitable carriers for parenteral administration of ATRA and other hydrophobic antitumor drugs, where the carriers are required to improve drug aqueous solubility and delay drug release almost after their accumulation in solid tumors.     

Inclusion complexation of metronidazole benzoate with β-cyclodextrin and its depression of anhydrate-hydrate transition in aqueous suspensions

Metronidazole benzoate was found to form an inclusion complex with β-cyelodextrin (β-CyD) in aqueous solution and in the solid phase. A phase solubility diagram was obtained and an apparent 1:1 formation complex constant of 1.3 × 10³ M^?1 was determined. A microcrystalline inclusion complex was isolated and shown to have the stoichiometric composition of 1:1.5 (drug: β-CyD). By inclusion complexation of the metronidazole ester with β-CyD the phase transition of the clinically used anhydrous form of the compound to the monohydrate occurring in aqueous suspensions was inhibited as was the marked crystal growth resulting from the phase transition. Besides increasing the physical stability of metronidazole benzoate suspensions the complexation with β-CyD protected the drug against photochemical degradation and decreased the rate of hydrolysis.     

非诺贝特与2种β-环糊精水溶性衍生物在水溶液中包合作用研究

目的研究羟丙基-β-环糊精（HP-β-CD）及磺丁基醚-β-环糊精（SBE-β-CD）在水溶液中对非诺贝特（fenofibrate,FNB）的包合作用。方法分别采用紫外吸收光谱法、相溶解度法研究HP-β-CD及SBE-β-CD在水溶液中对FNB的包合作用、增溶作用及包合过程中热力学参数的变化。结果 FNB与2种β-CD水溶性衍生物在水溶液中均存在明显的分子间相互作用。FNB的溶解度随着2种β-CD水溶性衍生物浓度的增加而呈线性增加,相溶解度图呈AL-型。包合过程中的热力学参数变化包括吉布斯自由能变化（ΔG）、焓变（ΔH）、熵变（ΔS）均为负值。结论 FNB与HP-β-CD及SBE-β-CD在水溶液中均可自发形成1：1克分子比可溶性包合物,从而增加其溶解度。同时,包合过程均为焓驱动过程,且为放热反应（ΔH〈0）,熵减过程（ΔS〈0）。适当降低温度将有利于包合过程的进行。     

Biochemical characterisation of para-aminophenol-induced nephrotoxic lesions in the F344 rat

The acute biochemical effects of the nephrotoxin p-aminophenol (PAP) were studied in detail using a combination of conventional bioanalytical and ¹H-NMR spectroscopic methods. Dosing PAP (25–100 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy with consequent elevations in urinary enzymes, glucose, and urine total protein as shown by conventional methodology. ¹H-NMR spectroscopy at 400 MHz of urine from PAP-treated rats also revealed a characteristic glycosuria, with concomitant amino aciduria. The increased excretion of these compounds indicates functional defects in the proximal tubule and reduced solute reabsorption efficiency. In addition, ¹H-NMR urinalysis and conventional enzymatic analysis showed a dose-related lactic aciduria. Other changes detected by ¹H-NMR included a dose-related reduction in the excretion of citrate (confirmed by a conventional biochemical method) and an increase in the excretion of acetate. The degree of abnormalities shown by ¹H-NMR urinalysis agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity. ¹H-NMR urinalysis therefore serves to highlight changes in the excretion of low MW urine components not routinely studied by conventional biochemical analysis.Abbreviations ALP alkaline phosphatase - APAP paracetamol - BUN blood urea nitrogen - GFR glomerular filtration rate - GOT glutamate oxaloacetate transaminase - LAP leucine aminopeptidase - LDH lactate dehydrogenase - MW molecular weight - NAG N-acetyl--D-glucosaminidase - PAP p-aminophenol - ppm parts per million - TMAO trimethylamine N-oxide - UFR urine flow rate     

吡罗昔康与β-环糊精包合物结构的核磁共振研究

本文采用¹HNMR和二维NOE等方法研究了吡罗昔康与β-环糊精包合物的结构。化学位移变化和NOE的结果提示,在溶液中二者的摩尔比为1:1时,主要是药物的苯环部份包藏在β-环糊精的空腔内。     

The Interaction Between Oxytetracycline and Divalent Metal Ions in Aqueous and Mixed Solvent Systems

The effects of pH, mixed solvent systems, and divalent metal ions on oxytetracycline (OTC) solubility and the interactions between OTC and metal ions in aqueous and mixed solvent systems were investigated. OTC solubility profiles were obtained for pH 4–9. The cosolvents studied were glycerin, propylene glycol, PEG 400, and 2-pyrrolidone with the following metal ions: magnesium, calcium, and zinc. OTC and its interactions with these metal ions were evaluated by solubility, NMR, circular dichroism (CD), and electron diffraction (ED) methods. At pH 5.6, no complexation occurred with these metal ions, but OTC zwitterion formed aggregates in aqueous solutions as shown by NMR spectra. The hydration of the metal ions was observed to affect OTC aggregation, with Mg⁺² causing the greatest OTC aggregation. At pH 7.5, OTC aggregation and metal–OTC complexation were observed in solutions with Ca⁺² and Mg⁺². Zinc ion was found to decrease OTC solubility because of zincate formation, which caused anionic OTC to precipitate. Electron diffraction revealed a relationship between OTC and metal–OTC complex crystallinity and solubility behavior. The zinc–OTC complex exhibited the highest crystallinity and lowest solubility at pH 8.0. Various cosolvents generally enhanced OTC solubility, with 2-pyrrolidone having the best solubility power. In OTC–metal-2-pyrrolidone and OTC–Zn⁺²-PEG 400 systems, circular dichroism provided evidence for the formation of soluble ternary complexes.     

Stacking complexation by nicotinamide: A useful way of enhancing drug solubility

The solubility enhancement of 11 poorly soluble drugs by complexation using nicotinamide has been studied. The solubilization efficiency of nicotinamide has been compared to that of hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin. Solubility enhancements as high as 4000-fold are observed in 20% (w/v) nicotinamide solution. Furthermore, nicotinamide is more effective than cyclodextrins for solubilizing some of the drugs. The mechanism of drug solubilization by nicotinamide is investigated by studying the effects of nicotinamide concentration on the surface tension and the conductivity of water. A slight break in both, the surface tension and conductivity is noticed at around 10% (w/v), suggesting self-association at higher concentrations. Corresponding breaks in the solubility profiles of estrone and griseofulvin at similar concentrations support self-association. Based on this observation it appears that at low concentrations, one molecule of nicotinamide undergoes complexation with one drug molecule to form a 1:1 complex. At higher concentrations, two molecules of nicotinamide undergo complexation with one drug molecule forming a 1:2 complex. The complexation constants have been calculated for all the drugs and the data are well described by this model. Expectedly, increasing the temperature reduces the complexation constants.     

Preparation,physicochemical characterization and biological evaluation of cefodizime metal ion complexes

Objectives Cefodizime is a broad spectrum cephalosporin belonging to the third generation agents. In this study, attention has been paid to the preparation, physicochemical characterization and biological evaluation of new Cu²⁺, Zn²⁺, Fe³⁺, Co²⁺ and Al³⁺ complexes of cefodizime. Methods The stoichiometrics and the mode of bonding of the complexes were deduced from their elemental and metal analysis, electrical conductivity measurements, UV‐vis, infrared and Raman spectroscopic investigations. Study of the stoichiometry of these complexes referred to the formation of 1: 1 ratios of metal to ligand. Antimicrobial activity of the complexes was determined using two strains of Gram‐positive (Bacillus subtilis and Proteus vulgaris) and two strains of Gram‐negative (Escherichia coli W3110 and Pseudomonas putida) bacteria. The minimal inhibitory concentration was determined as the lowest concentration inhibiting bacterial growth on solid Luria Bertani medium. Key findings The spectra gave evidence as to the position of binding. In addition, the aqueous solubility of cefodizime was strongly reduced by complexation. Conclusions The antibacterial activity of cefodizime was not affected by complexation with Al³⁺ but it was reduced by complexation with the other tested metal ions against the bacteria under study.     

Complexation of Hydrocortison with β-Cyclodextrin and Hydroxypropyl-β-Cyclodextrin

Hydrocortison (HC) forms water-soluble inclusion compounds with β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD), as proved by the equilibrium phase solubility diagrams and by ¹H-NMR spectroscopy. The solubility isotherm of the HC/βCD system is of the BS type, that of the HPβCD system of the AL type. The values of the complex stability constants are K = 4792 M^?1 and 1739 M^?1, respectively. 8 parallel preparations of solid HC/βCD complexes by coprecipitation resulted in a stoichiometric ratio of 0.49:1 which corresponds to a molar ratio of 1:2; the HC content is 13.2±0.2%. The ratio of the HC/HPßCD complex is 0.335 which equals a molar ratio of 1:3; the HC content is 8.6 ± 0.2%. The proof of inclusion formation was performed by X-ray diffractometry and thermoanalytical procedures (DSC, TG, thermofractography). We cannot exclude that some of the HC molecules are not included in the HPßCD cavity.     

2-Hydroxypropyl-β-cyclodextrin complexation with ursodeoxycholic acid

The complexation in aqueous medium and in the solid phase of ursodeoxycholic acid (UDCA) with a highly soluble cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, was studied by means of solubility methods, IR and 13C-NMR spectroscopy, X-ray diffractometry and thermal analysis. UDCA inclusion took place with 1:1 stoichiometry. ¹³C-NMR analysis suggested that the side chain was introduced into the cyclodextrin cavity. The UDCA/cyclodextrin complex showed better dissolution properties than plain drug crystals. Therefore, the complex may be used to improve the delivery and bioavailability of ursodeoxycholic acid.     

Novel non-acidic formulations of haloperidol complexed with β-cyclodextrin derivatives

Haloperidol (Hal), a highly hydrophobic drug, was complexed with two β-cyclodextrin (β-CD) derivatives. Hal solubility was increased 20-fold in the presence of a 10-fold excess of methyl β-CD (Meβ-CD) and 12-fold in the presence of a 10-fold excess of 2-hydroxypropyl β-CD (HPβ-CD). The stoichiometries and stability constants of Hal–Meβ-CD (1:1 and 2345 M⁻¹ at 27°C) and Hal–HPβ-CD (1:1 and 2112 M⁻¹ at 27°C) complexes were calculated by the continuous variation and phase solubility methods respectively. Differential scanning calorimetry and ¹H-NMR were used to confirm the formation of inclusion complexes. Moreover, the enthalpy and entropy of the complexation process were calculated for both complexes in order to obtain such information as the main `driving force' and whether or not complex formation is thermodynamically favoured. This was achieved by monitoring the isothermic solubility lines at various temperatures.     

Improvement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins

This study relates to the preparation of a series of amphiphilic dextrins and their evaluation as complexing agents for anti-tumor hydrophobic drugs such as fenretinide, paclitaxel, etoposide, and camptothecin. The amphiphilic dextrins were obtained by conjugation of low molecular weight dextrin (average molecular weight 1670, average polymerization degree 9.33 glucose monomer) with hydrocarbon chains at substitution degree of about 0.1 mole hydrocarbon chain per mole of glucose monomer, as confirmed by ¹H-NMR spectra. The conjugates were highly soluble in water and dissolved with formation of nano-aggregates endowed with hydrophobic inner cores able to host hydrophobic drugs by complexation. Complexation raised hydrophobic drugs aqueous solubility; the best results were obtained with fenretinide. Solid complexes with fenretinide were prepared by using three differents approaches: the kneading method, the co-solubilisation method, and the co-precipitation method. Kneading method provided the complexes endowed with the best functional properties. Thermogravimetric analysis on solid samples suggested a notable thermal stability up to 300°C for both the conjugated dextrins and the solid complexes. In differential scanning calorimetry profiles no significant differences were observed among amphiphilic dextrins and complexed drug, indicating that the guest molecule exists in an amorphous state in the solid matrices. Particle size analysis confirmed the dimensional suitability of the complexes for parenteral administration. Moreover, sustained drug release, in vitro, has been observed from all the complexes analyzed. Regarding the biological effects, the cytotoxicity of complexed fenretinide towards HTLA-230 neuroblastoma cell line was always higher than the free drug, suggesting that complexation increased drug bioavailability. These findings, taken together, indicated that these biodegradable, self-assembling dextrin conjugates may be regarded as new potential complexing agents for hydrophobic drugs and, in particular, for fenretinide, to increase drug solubility, bioavailability, and thus therapeutic efficacy.     

Solubility Enhancement of Nucleosides and Structurally Related Compounds by Complex Formation

Water-soluble vitamins, amino acids, and nontoxic pharmaceutical excipients were studied as solubilizing agents for poorly water-soluble adenine (nucleic acid base), guanosine (nucleoside), and structurally related drugs (acyclovir and triamterene). The apparent solubility of the substrates (adenine, guanosine, acyclovir, or triamterene) was appreciably increased by forming complexes with the ligands (vitamins, amino acids, or other ligand). Apparent association constants (K _a ) values were measured at 25°C in pH 7 phosphate buffer using phase solubility analysis. The effect of combination ligands on substrate solubility was also studied. Additive solubility enhancement was obtained for several ligand pairs.     

Alginate-Based Hydrogel Containing Minoxidil/Hydroxypropyl-β-Cyclodextrin Inclusion Complex for Topical Alopecia Treatment

Cutaneous minoxidil (MXD) formulations were developed with the intent to reduce the side effects of the cosolvents propylene glycol and ethanol, frequently used in commercial MXD solutions. Completely aqueous alginate-based hydrogels were investigated and MXD aqueous solubility was improved using inclusion complexes with hydroxypropyl-β-cyclodextrin (HP-β-CD) at 2 different molar substitution degree (MS), namely 0.65 and 0.85. HP-β-CD MS 0.65 was selected for its improved solubilizing ability toward MXD. At concentration of 39% w/v, this cyclodextrin increased the intrinsic aqueous solubility of MXD of about 22-fold. The calculated complexation constant was 2309 ± 20 M^?1, and the inclusion process was spontaneous and enthalpically driven. Nuclear magnetic resonance studies (Job plot, ¹H, 2D correlations spectroscopy, nuclear overhauser effect spectroscopy, and rotating-frame overhauser enhancement spectroscopy) confirmed the stoichiometry 1:1 between MXD and HP-β-CD providing information about the exact geometry of the inclusion complex. Rheological and in vitro release studies performed on the formulation loaded with MXD 3.5% w/w proved that the inclusion complex increased the viscosity of the hydrogel modulating the release of the free drug. Furthermore, the hydrogel formulation facilitate MXD to permeate into the skin and did not damage epidermis, suggesting that these completely aqueous MXD delivery systems can be proposed as alternative formulations to commercial solutions.     

Factors affecting solubilization of a poorly soluble novel tubulin-binding agent

JCA112 is a novel tubulin-binding agent with limited aqueous solubility and high hydrophobicity. Three strategies; cyclodextrin inclusion complexation, solid dispersion (SD) formation, and liposome incorporation were evaluated to enhance the solubility of JCA112. Phase-solubility studies were carried out with hydroxypropyl β-cyclodextrin (HPβCD), SDs were prepared by solvent evaporation method and liposomes were prepared by thin-film hydration method. Saturation solubility of the prepared formulations resulted in a significant increase in the solubility of JCA112 by all three methods. Cyclodextrin complexation resulted in a higher order complex formation increasing the aqueous solubility by 30-fold up to 105 μg/mL. Amongst the selected polymers, Poloxamer 188 (Pluronic^® F68) was the most effective polymer in enhancing the aqueous solubility via SD, resulting in an equilibrium solubility of 50 μg/mL, independent of the drug loading. Liposomes were the most effective amongst all three techniques, with a saturation solubility of 1.8 mg/mL contributing to greater than 500-fold increase in the solubility of JCA112. The solubility enhancement by liposome was directly proportional to the drug loading. All the three strategies were successful in enhancing the solubility of the drug. Solubility enhancement by the three techniques can be attributed to the geometry/structure and the lipophilicity of the drug.