Solubility properties of chlorhexidine salts

Chlorhexidine (CHX) is effective in treating oral bacterial infections. The solubility was shown to be highly dependent on the salt present in solution. Gluconate enhances the amount of CHX diacetate in solution possibly through mixed micelles formation, because the solubility product is such that the concentration of CHX will exceed the critical micelle concentration. However, only low concentrations of CHX dichloride can be obtained, which is not appreciably solubilized by gluconate ions. The low concentration of CHX that can be achieved in physiological concentrations of chloride in the oral cavity may be problematic for dental, slow release formulations.     

Design and evaluation in vitro of controlled release mucoadhesive tablets containing chlorhexidine

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Formation of persisters in <Emphasis Type="Italic">Streptococcus mutans</Emphasis> biofilms induced by antibacterial dental monomer

Antibacterial monomers can combat oral biofilm acids and caries; however, little is known on whether quaternary ammonium monomers (QAMs) would induce drug persistence in oral bacteria. The objectives of this study were to investigate the interactions of Streptococcus mutans (S. mutans) with dimethylaminohexadecyl methacrylate (DMAHDM), and determine for the first time whether DMAHDM could induce persisters in S. mutans. DMAHDM was synthesized using a modified Menschutkin reaction. Dose-dependent killing curves and time-dependent killing curves of planktonic S. mutans and biofilms were determined to evaluate drug persistence, using chlorhexidine (CHX) as control. The inheritability assay, minimum inhibitory concentration (MIC) and live/dead biofilm assay were determined to investigate persister characteristics. DMAHDM matched the killing potency of the gold standard CHX against S. mutans biofilms. DMAHDM and CHX induced drug persistence in S. mutans biofilms but not in planktonic bacteria. S. mutans biofilm persistence was not inheritable in that the tolerance to DMAHDM or CHX of the surviving persisters in the initial population was not transferred to subsequent generations, as displayed by the inheritability assay. The MIC of S. mutans parental strain and induced persisters remained the same. The induced persisters in S. mutans biofilms could be eliminated via higher doses of 300?μg/mL of DMAHDM and CHX. In conclusion, this study showed for the first time that (1) DMAHDM induced persisters only in biofilms, but not in planktonic bacteria; and (2) both DMAHDM-induced and CHX-induced S. mutans persister biofilms could be completely eradicated by even higher concentrations of DMAHDM and CHX. More studies are needed on the induction of persisters in oral biofilms for the development and use of a new generation of antibacterial dental monomers and resins.     

Design and Evaluation In Vitro of Controlled Release Mucoadhesive Tablets Containing Chlorhexidine

ABSTRACT

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

The solubility of Cr(III) and Cr(VI) compounds in soil and their availability to plants

The mystery surrounding high concentrations of Cr(III) in plants has been uncovered. It is attributed to the presence of low molecular weight organic acids (LMWOA) in soil in which the plants are growing. Apart from that, the factors influencing solubility of Cr(VI) in soil have also been investigated. It was found that the solubility of Cr(VI) species is governed by the presence of CO3(2-) ions in a soil solution that resulted when atmospheric CO2 dissolves in soil-water. Concentrations of Cr(VI) and Cr(III) were determined in plants, collected on unpolluted soils in different geographical areas. It was found that the concentration of Cr(VI) in plants correlated with the soluble fraction of Cr(VI) in soil, while Cr(III) concentration in plants is limited by concentration LMWOA in soil. It can therefore be concluded that the high level of Cr(III) in plants is also due to the direct absorptions of the species from soil rich in organic acids.     

Influencing factors on gelatin matrix for chlorhexidine delivery

Objective: The objective was to evaluate the influencing factors in the fabrication of gelatin matrix (gelatin chips) for drug delivery. The attributes affecting drug release characteristics of the gelatin products were examined.

Significance: Understanding the attributes that affect drug release from gelatin matrix could provide the knowledge base for the development, manufacturing, and performance evaluation of gelatin-based drug products for sustained drug delivery.

Methods: Chlorhexidine (CHX) was the model drug in the gelatin-product testing. The gelatin products were fabricated by two methods: a single-pot mixing of all the components and a two-step gelatin crosslinking followed by drug loading. Different gelatin types (Type A porcine and Type B bovine), glutaraldehyde (GTA) crosslinking conditions, glycerin concentration, and CHX concentration in drug loading and loading time were used to fabricate the products. The cumulative amounts of CHX release from the gelatin products were determined using in vitro release testing (IVRT).

Results: The attributes affecting CHX release from the gelatin products were gelatin type, GTA crosslinking, and CHX loading concentration. The fabrication methods (two-step method of gelatin crosslinking and drug loading by equilibration vs. direct mixing of the components) also affected CHX release. Other attributes such as glycerin and CHX loading time did not show significant effects on drug release under the conditions studied. In addition, the results in the two IVRT methods employed in this study were comparable.

Conclusion: Gelatin products of qualitative (Q1) and quantitative (Q2) differences could lead to different drug release behaviors. Drug release was also affected by the ingredient mixing steps during gelatin chip fabrication.     

Investigation of factors affecting in vitro doxorubicin release from PEGylated liposomal doxorubicin for the development of in vitro release testing conditions

Establishing appropriate drug release testing methods of liposomal products for assuring quality and performance requires the determination of factors affecting in vitro drug release. In this study, we investigated the effects of test conditions (human plasma lot, pH/salt concentration in the test media, dilution factor, temperature, ultrasound irradiation, etc.), and liposomal preparation conditions (pH/concentration of ammonium sulfate solution), on doxorubicin (DXR) release from PEGylated liposomal DXR. Higher temperature and lower pH significantly increased DXR release. The evaluation of DXR solubility indicated that the high DXR release induced by low pH may be attributed to the high solubility of DXR at low pH. Ultrasound irradiation induced rapid DXR release in an amplitude-dependent manner. The salt concentration in the test solution, human plasma lot, and dilution factor had a limited impact on DXR-release. Variations in the ammonium sulfate concentration used in solutions for the formation/hydration of liposomes significantly affected DXR release behavior, whereas differences in pH did not. In addition, heating condition in phosphate-buffered saline at lower pH (<6.5) exhibited higher discriminative ability for the release profiles from various liposomes with different concentrations of ammonium sulfate than did ultrasound irradiation. These results are expected to be helpful in the process of establishing appropriate drug release testing methods for PEGylated liposomal DXR.     

Preparation and optimization of a novel microbead formulation to improve solubility and stability of curcumin

Curcumin is an active ingredient which is poorly water-soluble, leading to a low oral bioavailability. The aim of this research was to prepare a novel microbead formulation, and to solubilize, solidify, and improve storage stability of curcumin. Firstly, curcumin was solubilized with Kolliphor^TM RH40 and then microencapsulated by cross linking of sodium alginate with calcium chloride. A three-factor, three-level Box–Behnken design was employed to acquire the optimum microbead formulation, namely the best entrapment efficiency and in vitro curcumin release. The independent variables were sodium alginate concentration, calcium chloride concentration, and the weight of curcumin solution, while the dependent variables were entrapment efficiency and in vitro curcumin release. The optimized microbead formulation was 2.06% sodium alginate, 24.33% calcium chloride, and 1.28 g curcumin solution (containing curcumin and RH40 with a ratio of 1:22, g/g). Results showed that high concentrations of sodium alginate and calcium chloride could increase the entrapment efficiency. In vitro curcumin release decreased with increasing of sodium alginate as well as decreasing of calcium chloride. In conclusion, the optimum microbead formulation increased the solubility of curcumin and enhanced its stability, and achieved a high entrapment efficiency and in vitro curcumin release.     

Study in bactericidal properties of chlorhexidine grafting on the modified titanium

Chlorhexidine (CHX) is widely used in a number of dental applications to reduce inflammation as well as swelling of gums and gum bleeding. We investigate anti-adherent effect of CHX grafted titanium on oral pathogens such as S. mutans and S. aureus respectively. CHX grafted titanium surfaces show good anti-adherent properties.     

Apparent solubility of drugs in partially crystalline systems

Using several griseofulvin samples, representing different solid-state structures, the solubility behavior of drugs in both one-state (totally ordered, semiordered or disordered) and two-state systems was studied. Special attention was directed towards the surface structure of the particles. The partially crystalline samples were obtained by milling the raw material (crystalline standard) or storing the quenched sample (amorphous standard). The solid-state structure of the materials was studied using x-ray diffraction (XRD), differential scanning calorimetry (DSC), isothermal microcalorimetry (IMC), and scanning electron microscopy (SEM). The saturation concentration of the materials was studied in suspensions containing different dispersion concentrations of drug after centrifugation and filtration, using spectrophotometry. In all cases these dispersion concentrations exceeded the solubility of the drug. The solubilities were plotted vs. dispersion concentrations for each sample. Several solubility plateaus were found. The lowest and highest solubility plateaus corresponded to the solubilities of crystalline and amorphous standards. These plateaus were reached at 8 and 44 µg/mL for crystalline and amorphous griseofulvin standards, respectively. An intermediate plateau served as an indication of the existence of a totally semiordered structure. This was reached at 19 µg/mL for griseofulvin. Any deviation from these plateaus was suggested to be indicative of the existence of heterogeneity on the surface structure, which in most cases could be described as a two state system. In such cases, the apparent solubility was a function of dispersion concentration, until at very high dispersion concentrations (4000-20,000 µg/mL) the saturation concentration of the totally disordered (44 µg/mL) or semiordered (19 µg/mL) one-state phase was reached. No reduction in these values was observed during storage for 50 days. It is thus concluded that, in partially crystalline systems, the saturation concentration is an interfacial phenomenon, which depends on the amount, reactivity, and solid-state structure of the exposed solid surfaces in equilibrium with the solution. A simplified solubility model is proposed to qualitatively describe the relationship between established apparent solubilities (saturation concentrations) and different combinations of solid-state structures.     

Apparent Solubility of Drugs in Partially Crystalline Systems

Abstract

Using several griseofulvin samples, representing different solid-state structures, the solubility behavior of drugs in both one-state (totally ordered, semiordered or disordered) and two-state systems was studied. Special attention was directed towards the surface structure of the particles. The partially crystalline samples were obtained by milling the raw material (crystalline standard) or storing the quenched sample (amorphous standard). The solid-state structure of the materials was studied using x-ray diffraction (XRD), differential scanning calorimetry (DSC), isothermal microcalorimetry (IMC), and scanning electron microscopy (SEM). The saturation concentration of the materials was studied in suspensions containing different dispersion concentrations of drug after centrifugation and filtration, using spectrophotometry. In all cases these dispersion concentrations exceeded the solubility of the drug. The solubilities were plotted vs. dispersion concentrations for each sample. Several solubility plateaus were found. The lowest and highest solubility plateaus corresponded to the solubilities of crystalline and amorphous standards. These plateaus were reached at 8 and 44 µg/mL for crystalline and amorphous griseofulvin standards, respectively. An intermediate plateau served as an indication of the existence of a totally semiordered structure. This was reached at 19 µg/mL for griseofulvin. Any deviation from these plateaus was suggested to be indicative of the existence of heterogeneity on the surface structure, which in most cases could be described as a two state system. In such cases, the apparent solubility was a function of dispersion concentration, until at very high dispersion concentrations (4000–20,000 µg/mL) the saturation concentration of the totally disordered (44 µg/mL) or semiordered (19 µg/mL) one-state phase was reached. No reduction in these values was observed during storage for 50 days. It is thus concluded that, in partially crystalline systems, the saturation concentration is an interfacial phenomenon, which depends on the amount, reactivity, and solid-state structure of the exposed solid surfaces in equilibrium with the solution. A simplified solubility model is proposed to qualitatively describe the relationship between established apparent solubilities (saturation concentrations) and different combinations of solid-state structures.     

钒电池负极电解液V2（SO4）3溶解性规律

对钒电池负极电解液中活性物质V(III)在不同硫酸浓度、不同温度条件下的溶解性规律进行了深入研究,同时对V(III)-H2SO4体系电化学性能进行了初步探讨.结果表明:V(III)的溶解是一个放热过程,在15~40℃范围内,V(III)的溶解度随着温度升高而逐渐降低;并且溶液中V(III)会以V O V形式形成二聚体,在低硫酸浓度下,V(III)可以高浓度长时间稳定存在,随硫酸浓度的增大,V(III)溶解度逐渐降低,其中30℃、1 mol/L H2SO4条件下V(III)浓度可高达2.730 mol/L;进一步通过电化学测试,发现V(III)-H2SO4体系是不可逆体系,H2SO4浓度的增大有益于提高V(III)/V(II)氧化还原反应的可逆性.     

Enhanced oral bioavailability of ibuprofen in rats by poloxamer gel using poloxamer 188 and menthol

To improve the oral bioavailability of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution and pharmacokinetic study of ibuprofen delivered by the ibuprofen-loaded preparations composed of poloxamer 188 and menthol were then performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6 followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that four parts menthol formed eutectic mixture with six parts ibuprofen. In the presence of poloxamer, the solutions with the same ratio of menthol to ibuprofen showed an abrupt increase in the solubility of ibuprofen. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/mL. The simultaneous addition of menthol and poloxamer 188 significantly improved the dissolution rates of ibuprofen from aqueous solution due to the ibuprofen solubility-improving effect of menthol in the presence of poloxamer. Furthermore, the ibuprofen-loaded preparation with menthol and poloxamer 188 gave significantly higher initial plasma concentrations, Cmax, and AUC of ibuprofen than did the preparation without menthol and poloxamer 188, indicating that the simultaneous addition of menthol and poloxamer 188 could improve the oral bioavailability of ibuprofen in rats. In modern pain management it is always desirable for the ibuprofen-loaded preparation with poloxamer 188 and menthol to show a rapid onset of action with a minimal phase of lag time to feel the decreased pain. From an industry point of view, it is more desirable for a formulation to be fast acting, easy to use, and cost effective. Thus, the ibuprofen-loaded preparation with poloxamer 188 and menthol was a more effective oral dosage form for poorly water-soluble ibuprofen.     

Enhanced Oral Bioavailability of Ibuprofen in Rats by Poloxamer Gel Using Poloxamer 188 and Menthol

To improve the oral bioavailability of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution and pharmacokinetic study of ibuprofen delivered by the ibuprofen-loaded preparations composed of poloxamer 188 and menthol were then performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6 followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that four parts menthol formed eutectic mixture with six parts ibuprofen. In the presence of poloxamer, the solutions with the same ratio of menthol to ibuprofen showed an abrupt increase in the solubility of ibuprofen. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/mL. The simultaneous addition of menthol and poloxamer 188 significantly improved the dissolution rates of ibuprofen from aqueous solution due to the ibuprofen solubility-improving effect of menthol in the presence of poloxamer. Furthermore, the ibuprofen-loaded preparation with menthol and poloxamer 188 gave significantly higher initial plasma concentrations, Cmax, and AUC of ibuprofen than did the preparation without menthol and poloxamer 188, indicating that the simultaneous addition of menthol and poloxamer 188 could improve the oral bioavailability of ibuprofen in rats. In modern pain management it is always desirable for the ibuprofen-loaded preparation with poloxamer 188 and menthol to show a rapid onset of action with a minimal phase of lag time to feel the decreased pain. From an industry point of view, it is more desirable for a formulation to be fast acting, easy to use, and cost effective. Thus, the ibuprofen-loaded preparation with poloxamer 188 and menthol was a more effective oral dosage form for poorly water-soluble ibuprofen.     

温度、浓度对水/乙醇混合溶剂中壳聚糖溶液黏度的影响

研究了溶解于水/乙醇混合溶剂中的壳聚糖溶液黏度随温度和浓度的变化规律。混合溶剂中,乙醇是壳聚糖的不良溶剂,而水是壳聚糖的良溶剂,将乙醇与水按一定比例混合,再加入1%的乙酸,配制成水/乙醇混合溶剂。实验使用乌氏黏度计测量溶液黏度,通过分析黏度随温度、浓度的变化规律,揭示了混合溶剂对壳聚糖溶液黏度的影响规律。研究发现,壳聚糖溶液黏度随着温度的升高而降低;恒定温度,壳聚糖溶液黏度随浓度的增加而增加。而随着温度的升高,壳聚糖在良溶剂中产生的增比黏度变化率要比其在不良溶剂中高;随着浓度的增加,壳聚糖溶液产生的增比黏度的变化率也相应增加。当浓度极稀时,壳聚糖溶液的(ηsp/C)/C曲线会出现反常现象——体系黏度随着浓度的减小而急剧上升。     

Amorphous solid dispersion successfully improved oral exposure of ADX71943 in support of toxicology studies

ADX71943 is a potent and selective GABA_b receptor positive allosteric modulator (PAM) which exhibits poor aqueous solubility at all physiologically relevant pHs. The aim of this study was to identify an adequate formulation to improve the solubility of ADX71943 to achieve a sufficiently high plasma exposure after oral administration to support the toxicology program. Considering the overall physicochemical properties and the low solubility of ADX71943 in a variety of solvents, solid dispersion, and particle size reduction have been successfully chosen as potential strategies to improve its oral bioavailability. Both technologies have proven useful in improving the in vitro dissolution profile and as a result of the solubility enhancement, higher bioavailability was obtained in vivo. As the solid dispersion gave better bioavailability (30-fold compared with the neat active pharmaceutical ingredient (API)), this formulation was selected for the toxicology study. Changing the crystalline form of ADX71943 into amorphous state by preparing a solid dispersion has greatly improved its oral bioavailability and has allowed achieving the required plasma concentration needed in toxicology studies.     

Buccal tablets containing cysteine and chlorhexidine for the reduction of acetaldehyde levels in the oral cavity

There is growing evidence that a large proportion of upper digestive tract tumors are ascribable to heavy alcohol drinking and tobacco consumption. The cancer-promoting action of ethanol is mediated by acetaldehyde, its first metabolite, also derived from the bacterial oxidation of alcohol by the oral microflora, classified by the International Agency for the Research on Cancer as a carcinogen. Acetaldehyde is also one of the major components of tobacco smoke. These findings suggest two different strategies to decrease the risk of alcohol-related oral cancers: the reduction of the levels of alcohol-derived acetaldehyde in saliva and the reduction of oral bacterial flora. Therefore, the aim of our study was to develop and characterize some buccal tablet formulations containing both 20?mg l-cysteine hydrochloride (able to chemically neutralize acetaldehyde) and 10?mg chlorhexidine diacetate (well-known antiseptic compound active against a large spectrum of oral microbes). One of these formulations, chosen on the basis of its favourable delivery kinetics of the active principles, was demonstrated to be able to reduce acetaldehyde concentration in an in vitro system and to lower its salivary levels in volunteers after ethanol contact. Our findings support the hypothesis that the application of buccal devices containing cysteine and chlorhexidine could reduce salivary acetaldehyde levels and thus the incidence of upper gastrointestinal cancer in drinkers and smokers.     

Studies on acyclovir-dextran conjugate: synthesis and pharmacokinetics

Acyclovir is an antivirus drug which has a good in vitro activity against hepatitis B virus. But because of the low solubility and low distribution in liver, the clinical application of acyclovir in hepatitis B was limited. To increase the solubility and the distribution in liver, acyclovir-dextran conjugate was synthesized by formation of Schiff's base. The solubility of obtained conjugate was 12 times greater than free acyclovir. Acyclovir will be slowly released from the obtained conjugate in pH 7.4 phosphate buffer solution (PBS) at 37°C with a rate constant of 0.0035 hr^- 1. Pharmacokinetic studies of acyclovir and acyclovir-dextran conjugate were conducted in mice by i. v. administration. Acyclovir concentrations in plasma, liver and kidney were determined by HPLC method. Relatively higher distribution of acyclovir in liver was observed when i. v. acyclovir-dextran conjugate as compared with i.v. free acyclovir. The results of pharmacokinetic studies indicated that acyclovir-dextran conjugate will be a good candidate to treat hepatitis B.     

Formulation and delivery strategies of ibuprofen: challenges and opportunities

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is mostly administered orally and topically to relieve acute pain and fever. Due to its mode of action this drug may be useful in the treatment regimens of other, more chronic conditions, like cystic fibrosis. This drug is poorly soluble in aqueous media and thus the rate of dissolution from the currently available solid dosage forms is limited. This leads to poor bioavailability at high doses after oral administration, thereby increasing the risk of unwanted adverse effects. The poor solubility is a problem for developing injectable solution dosage forms. Because of its poor skin permeability, it is difficult to obtain an effective therapeutic concentration from topical preparations. This review aims to give a brief insight into the status of ibuprofen dosage forms and their limitations, particle/crystallization technologies for improving formulation strategies as well as suggesting its incorporation into the pulmonary drug delivery systems for achieving better therapeutic action at low dose.     

Interactive grain boundary segregation of nickel and antimony in iron

Abstract

A study of the grain boundary segregation of nickel and antimony in iron is reported in the present paper. It is shown by the results that antimony segregation increases as the bulk nickel and antimony concentrations increase. However, once the solubility limit for antimony in iron is exceeded, the amount of segregation remains essentially constant. Segregation of nickel in iron increases as the bulk concentration of nickel increases and as the bulk concentration of antimony increases. The last effect is observed only when a certain level of antimony is reached, a level that depends on the concentration of nickel. Small additions of antimony, even though they cause an increase in segregation of antimony, do not cause an increase in segregation of nickel and, once the solubility limit for nickel in Fe–Sb alloys is exceeded, the segregation of nickel reaches a plateau. It is only between these two regimes that segregation of nickel is affected by changes in the concentration of antimony. All these results can be explained based on the mutual effects that nickel and antimony have on the solubility of each in iron. The results are not consistent with models based on cosegregation. Finally, other data in the literature are examined; all these data can be explained by an argument based on solubility changes.

MST/795