New Ideas about the Solubility of Drugs

Methods are described for detecting precipitation of ionisable drugs under conditions of changing pH, estimating kinetic solubility from the onset of precipitation, and measuring solubility by chasing equilibrium. Definitions are presented for kinetic, equilibrium, and intrinsic solubility of ionisable drugs, supersaturation and subsaturation, and for chasers and non‐chasers, which are two classes of ionisable drug with significantly different solubility properties. The use of Bjerrum Curves and Neutral‐Species Concentration Profiles to depict solubility properties are described and illustrated with case studies showing super‐dissolving behaviour, conversion between crystalline forms and enhancement of solubility through supersaturation, and the use of additives and simulated gastrointestinal fluids.     

Solubility of nickel oxide particles in various solutions and rat alveolar macrophages

The solubility of five types of commercial nickel oxide particles was determined in different types of solutions, including distilled water, physiological saline, buffered saline, and tissue-culture medium, in order to estimate their solubility in the human respiratory tract. In addition, we examined the solubility of the two types of particles that were the most and least soluble particles of the above five types of nickel oxide, in rat alveolar macrophages cultured in vitro. The solubility of the nickel oxide particles in these solutions varied remarkably with their types, suggesting that, even though they are called as “nickel oxide,” their solubilities are different among the manufacturer and the product lot. Their solubilities were also influenced by the types of solution and the existence of carbon dioxide in the atmosphere. The solubility of nickel oxide particles in the alveolar macrophages was significantly larger than that observed in the culture medium without macrophages, but smaller than that observed in the distilled water. These results suggest that the actual solubility of nickel oxide particles in the respiratory tract may be difficult to estimate by the conventional solubility analysis method using distilled water, and that the enhancement of particle dissolution by the alveolar macrophages and the depression of particle solubility by the coexisting salt and carbon dioxide should be taken into consideration for the accurate estimation.     

Aqueous solubility of a simple (single-carbon) organic molecule as a function of its size &; dipole moment

The aqueous solubility of a single-carbon organic molecule as a function of its size & dipole moment was investigated. The molecular dipole moment was chosen to represent the polar character of a poly-atomic molecule. It is hypothesized here that at a given pH, temperature, and pressure, the solubility of a single-carbon organic molecule in water will be a function of its polar character; namely, dipole moment and of its molecular size. Different forms of the solubility function were tested; it was found that the solubility model, given by Eq. 1, which is based on the polar character and the molecular volume, adequately described the aqueous solubility of single-carbon organic moieties. The aqueous solubility of single-carbon organic solutes exhibits maximum at the condition of high polar character (large dipole moment) and low molecular volume. The general trend of the solubility of single-carbon organic solutes, based on the proposed model (Eq. 1) could be explained in terms of the trade-off between the driving force (degree of polar character of the solute) for solubilization versus the resistance to be solubilized as a result of the entropic effects which increase with increasing molecular volume of the organic moiety.     

Aqueous solubility of a diatomic molecule as a function of its size &; electronegativity difference

The aqueous solubility of a diatomic molecule as a function of its size & electronegativity difference is investigated. The electronegativity of a diatomic molecule will be calculated using five different electronegativity scales, namely, Pauling [1], Allred-Rochow [2], Mulliken [3, 4], Parr-Yang [5], and Sanderson [6, 7]. It is hypothesized here that at a given pH, temperature, and pressure, the solubility of a diatomic molecule in water will be a function of its polar character; in particular, electronegativity difference and of its molecular size. Different forms of the solubility function were tested; it was found that the solubility model, given by Eq. 3, which is based on different electronegativity scales and the molecular volume, adequately describes the aqueous solubility of alkali halides. The aqueous solubility of alkali halides exhibits maximum at the condition of high electronegativity difference and large molecular volume. On the other hand, the minimum solubility region is observed at very low molecular volume and medium to slightly high values of electronegativity difference. The minimum solubility is also observed at low value of electronegativity difference and high molecular volume. Finally, the general trend of solubility of alkali halides, based on the proposed model (Eq. 3) could be explained in terms of the trade-off between electrostatic interactions (solid lattice side) and the entropic effects (water side).     

Solubility evaluation of murine hybridoma antibodies

The successful development of antibody therapeutics depends on the molecules having properties that are suitable for manufacturing, as well as use by patients. Because high solubility is a desirable property for antibodies, screening for solubility has become an essential step during the early candidate selection process. In considering the screening process, we formed a hypothesis that hybridoma antibodies are filtered by nature to possess high solubility and tested this hypothesis using a large number of murine hybridoma-derived antibodies. Using the cross-interaction chromatography (CIC) method, we screened the solubility of 92 murine hybridoma-derived monoclonal antibodies and found that all of these molecules exhibited CIC profiles that are indicative of high solubility (>100mg/mL). Further investigations revealed that variable region N-linked glycosylation or isoelectric parameters are unlikely to contribute to the high solubility of these antibodies. These results support the general hypothesis that hybridoma monoclonal antibodies are highly soluble.     

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

The objective of this study was to investigate the pH-dependent solubility and dissolution of weakly basic Biopharmaceutical Classification Systems (BCS) class II drugs, characterized by low solubility and high permeability, using carvedilol, a weak base with a pK _a value of 7.8, as a model drug. A series of solubility and in vitro dissolution studies was carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH range of the GI from 1.2 to 7.8. The effect of ionic strength, buffer capacity, and buffer species of the dissolution media on the solubility and dissolution behavior of carvedilol was also investigated. The study revealed that carvedilol exhibited a typical weak base pH-dependent solubility profile with a high solubility at low pH (545.1–2591.4 μg/mL within the pH range 1.2–5.0) and low solubility at high pH (5.8–51.9 μg/mL within the pH range 6.5–7.8). The dissolution behavior of carvedilol was consistent with the solubility results, where carvedilol release was complete (95.8–98.2% released within 60 min) in media simulating the gastric fluid (pH 1.2–5.0) and relatively low (15.9–86.2% released within 240 min) in media simulating the intestinal fluid (pH 6.5–7.8). It was found that the buffer species of the dissolution media may influence the solubility and consequently the percentage of carvedilol released by forming carvedilol salts of varying solubilities. Carvedilol solubility and dissolution decreased with increasing ionic strength, while lowering the buffer capacity resulted in a decrease in carvedilol solubility and dissolution rate.     

Impacts of Sample Preparation Methods on Solubility and Antilisterial Characteristics of Essential Oil Components in Milk

Essential oil components (EOCs) have limited water solubility and are used at much higher concentrations in complex food matrices than in growth media to inhibit pathogens. However, the correlation between solubility and activity has not been studied. The objective of this work was to characterize the solubility of EOCs in solvents and milk and correlate solubility with antilisterial activity. The solubilities of four EOCs, thymol, carvacrol, eugenol, and trans-cinnamaldehyde, in water was significantly increased in the presence of 5% (vol/vol) ethanol. In milk, the solubility of EOCs was lower than in water, with lower solubility in higher-fat milk. EOCs applied to milk as stock solutions (in 95% aqueous ethanol) enabled quicker dissolution and higher solubility in milk serum than other methods of mixing, such as end to end, and greater reductions of Listeria monocytogenes Scott A after 0 and 24 h. When the EOC concentration detected in milk serum was above the minimum bactericidal concentration, complete inhibition of L. monocytogenes in tryptic soy broth resulted. Therefore, the antilisterial properties in milk could be correlated with the solubility by comparison to the minimum inhibitory or bactericidal concentrations of EOCs. While the EOCs applied using ethanol generally had solubility and activity characteristics superior to those of other mixing methods, ethanol is not used to a great extent in nonfermented foods. Therefore, mixing methods without an organic solvent may be more readily adaptable to enhancing the distribution of EOCs in complex food systems.     

可溶性细胞间粘附分子-1在新生儿缺氧缺血性脑病血清中的表达及临床意义

目的：探讨可溶性细胞间粘附分子-1（ICAM-1）在新生儿缺氧缺血性脑病（HIE）血清中的表达及其与病情严重程度的关系。方法：采用酶联免疫吸附双抗体夹心法（ELISA）检测45例HIE新生儿和50例健康新生儿血清中可溶性ICAM-1水平。结果：HIE组血清可溶性ICAM-1浓度为（159．25±25．62）ng／ml,对照组血清可溶性ICAM-1浓度为（53．35±12．42）ng／ml,两组相比较有显著性并差异（P〈0．05）;轻、中、重度HIE患儿血清可溶性ICAM-1浓度与对照组比较显著升高（P〈0．05）,在HIE各组中可溶性ICAM-1浓度为重度〉中度〉轻度,各组相比较有显著性差异（P〈0．05）;HIE患儿血清可溶性ICAM-1水平与临床分度呈正相关相关（r=0．652,P〈0．01）。结论：可溶性ICAM-1在HIE新生儿血清中呈高表达,可溶性ICAM-1的水平与病情严重程度密切相关。可溶性ICAM-1在新生儿缺氧缺血性脑损伤中起着重要作用：     

Imidacloprid and Related Compounds: Structure and Water Solubility of N-Alkyl Derivatives of Imidacloprid

An intramolecular hydrogen bond between NH???O₂N in insecticide, imidacloprid (1), and its nitromethylene analog 15 was proved by NMR and IR spectra. That electron delocalization over their planar moieties was disrupted by alkylation at the imidazolidine nitrogen atom is demonstrated by the hypsochromic shifts in UV and deshielding effect in NMR spectra. Interestingly, the N-alkyl derivatives (C1-5) had greater water solubility than 1, although increasing alkyl chain length decreased the solubility. The hydrophilicity of the alkyl derivatives would result from remote charge heads being formed as a result of the conjugation disruption by alkylation, while the hydrophobicity of 1 could be ascribed to the charge distribution over the conjugated system coupled with the intramolecular H-bonding. The greater water solubility of 15 than 1 and contrastively small solubility of the cyanoimine analogue are discussed based on the difference in their steric crowding.     

Solubility evaluation of murine hybridoma antibodies

The successful development of antibody therapeutics depends on the molecules having properties that are suitable for manufacturing, as well as use by patients. Because high solubility is a desirable property for antibodies, screening for solubility has become an essential step during the early candidate selection process. In considering the screening process, we formed a hypothesis that hybridoma antibodies are filtered by nature to possess high solubility and tested this hypothesis using a large number of murine hybridoma-derived antibodies. Using the cross-interaction chromatography (CIC) method, we screened the solubility of 92 murine hybridoma-derived monoclonal antibodies and found that all of these molecules exhibited CIC profiles that are indicative of high solubility (>100mg/mL). Further investigations revealed that variable region N-linked glycosylation or isoelectric parameters are unlikely to contribute to the high solubility of these antibodies. These results support the general hypothesis that hybridoma monoclonal antibodies are highly soluble.     

In vitro digestion method to evaluate solubility of dietary zinc,selenium and manganese in salmonid diets

BackgroundThe determination of dietary mineral solubility is one of the main steps in the evaluation of their availability for a given species.MethodsThis study proposed an in vitro digestion method (acidic and alkaline hydrolysis). The method was applied to evaluate the solubility of inorganic and organic forms of zinc (Zn), selenium (Se) and manganese (Mn) in salmonid diets. An inorganic mineral (IM) diet was supplemented with zinc sulphate, sodium selenite and manganous sulphate and an organic mineral (OM) diet was supplemented with zinc chelate of glycine, l-selenomethionine and manganese chelate of glycine.ResultsThe solubility of Zn was similar in both diets tested. The amount of soluble Zn was low in the acidic hydrolysis (3–8%) and lower in the alkaline hydrolysis (0.4–2%). The solubility of Se was higher in the OM diet (7–34%) compared with the IM diet (3–12%). Regarding Mn, after the acidic hydrolysis the solubility was higher in the IM diet (6–25%) than the OM diet (4–17%). The in vitro solubility were compared with in vivo availability of Zn, Se and Mn. Data obtained for solubility (%) of Zn, Se and Mn was lower when compared with apparent availability (%) of Zn, Se and Mn.ConclusionData obtained demonstrated that solubility of Zn, Se and Mn was influenced by the mineral chemical form supplemented to the diet and by the gastrointestinal environment. The solubility of Zn, Se and Mn was not comparable with the apparent availability of Zn, Se and Mn. Nevertheless, the effect of the chemical form of the minerals was similar for the solubility of Zn, Se and Mn and the apparent availability of Zn, Se and Mn. Considering the overall results of this study, the in vitro method could replace some of the in vivo studies for a qualitative evaluation but not for a quantitative evaluation.     

Evaluation of the Membrane Permeability (PAMPA and Skin) of Benzimidazoles with Potential Cannabinoid Activity and their Relation with the Biopharmaceutics Classification System (BCS)

The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P _oct value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).     

黄芩苷溶解性能的测定与表征

目的：充分了解黄芩苷的溶解性质,为黄芩苷类制剂的研究设计提供依据。方法：采用HPLC法测定黄芩苷在各溶媒中的溶解度,考察温度、pH值、表面活性剂等对其溶解度的影响,利用溶度参数理论探讨其溶解性能理论及表征其溶解性能。结果：黄芩苷在水中属几乎不溶的范畴;溶解度随着温度升高和pH值的增加而升高,溶解过程是吸热的,溶解度与温度的关系方程线性关系良好,可用于预测黄芩苷在设定温度下的溶解度;吐温80可提高黄芩苷的增溶度;黄芩苷在各溶媒中的溶解度大小与利用溶度参数表征黄芩苷溶解性能的结果吻合。结论：黄芩苷水溶性差、脂溶性均较差,可通过升温、调节pH值及加表面活性剂改变黄芩苷的溶解性质,可利用溶度参数理论对黄芩苷的溶解性能进行表征。     

Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate

We determined the experimental solubility of CNS marketed drugs. Of the 98 drugs measured, greater than 90% had solubility >10 μM in pH 7.4 buffer. Only seven drugs had solubility <10 μM. Using these data, we established a solubility criterion to support CNS discovery. The implication of poor solubility with potential safety concerns and undesirable side effects are discussed.     

Effect of Cyclodextrin Complexation on the Aqueous Solubility and Solubility/Dose Ratio of Praziquantel

Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of β-CD and HP-β-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.     

Solubility Enhancement of Lovastatin by Modified Locust Bean Gum Using Solid Dispersion Techniques

The aim of the present study was to improve the solubility of poorly water soluble drug lovastatin (LS) by solid dispersion (SD) techniques using modified locust bean gum (MLBG) as a carrier. The locust bean gum (LBG) was modified by heating and there observed irreversible decrease in viscosity, whereas swelling property remains unaffected. The advantage of modification of LBG was illustrated by difference in dissolution profiles of their SD. Effect of polymer concentration and methods of preparation on solubility enhancement were studied using solubility and dissolution studies, respectively. The result of solubility study showed increase in solubility of LS with increase in concentration of MLBG. It was found that the dissolution rate of LS from its SD was dependent on the method of preparation of solid dispersions. Dissolution study revealed that the modified solvent evaporation is most convenient and effective method for solubility enhancement of poorly water soluble drug LS, among various methods of preparation of SD. The prepared SDs were characterized by differential scanning calorimetry, scanning electron microscopy, and X-ray diffraction study. In vivo study was performed by measuring 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG Co-A) reductase inhibition activity. Significant reduction in HMG Co-A reductase activity was observed in case of solid dispersions of LS than plain LS. In conclusion, MLBG could be used as a potential carrier in enhancing the dissolution rate and bioavailability of LS.     

Upregulation of p53 through induction of MDM2 degradation: Amino acid prodrugs of anthraquinone analogs

Previously, we reported a class of MDM2-MDM4 dimerization inhibitors that upregulate p53 and showed potent anticancer activity in animal models. However, water solubility hinders their further development. Herein we describe our effort to develop a prodrug approach that overcomes the solubility problem. The prodrug of BW-AQ-238, a potent anthraquinone analog, was made by esterification of the hydroxyl group with various natural amino acids. Cytotoxicity of these compounds toward Hela and EU-1 cells, their aqueous solubility, and the release kinetics of these prodrugs in buffer and in the presence of hydrolytic enzymes were studied. The results demonstrate that the amino acid prodrug approach significantly improved the water solubility while maintaining the potency of the parent drug.     

Synergistic effect of PEG-400 and cyclodextrin to enhance solubility of progesterone

Conclusion  PEG-400, polysorbate 80, and 2 CDs (Trappsol HPB and Captisol) were used in an attempt to improve the aqueous solubility of a model hydrophobic drug, progesterone. The aqueous solubility of progesterone improved significantly from 0.007 mg/mL by the addition of PEG-400, CDs, and polysorbate 80. In systems containing various amounts of PEG-400 and 3% Trappsol HPB in water (% wt/wt), the theoretical solubility was calculated by adding the solubilities in the individual systems. The observed solubility values were up to 96% higher than the theoretical values. The effect of synergism was significant in 5% to 50% PEG-400/water systems containing Trappsol HPB. Systems containing Captisol did not show such synergistic effects. In general, the addition of polysorbate 80 to the PEG-400/water systems containing CDs affected synergism negatively.     

Effects of ethanol and 3,4,-dihydron-2,2-dimethyl-2h-1-benzopyran-6-butyric acid on the solubility of sickle hemoglobin.

The effect of 3,4-dihydro-2,2-dimethyl-2H-1 benzopyran-6-butyric acid (DBA) on the solubility of deoxy-Hb S was evaluated by measuring saturation concentration, c_sat. Plots of c_sat versus DBA concentration in the presence or absence of ethanol gave two parallel lines, indicative of the additive fashion in which ethanol and DBA increase the solubility of deoxy-Hb S. At a $\text{DBA}\text{Hb}$ molar ratio of 10:1, c_sat was increased 16%. Ethanol alone increased c_sat comparably, but at a much higher molar excess (200:1). DBA had no effect on the oxygenation parameters of Hb S. Complementary solubility studies using the salting-out method showed that DBA had no effect on deoxy-Hb S, but decreased the solubility of deoxy-Hb A, oxy-Hb A and oxy-Hb S. Hence, no correlation exists between the effect of DBA on the solubility of deoxy-Hb S measured as c_sat and that measured by the salting-out technique.