Co-solvent solubilization of some poorly-soluble antidiabetic drugs

Co-solvent solubilization approach has been used to enhance the solubility of seven antidiabetic drugs: gliclazide, glyburide, glipizide, glimepiride, repaglinide, pioglitazone, and roziglitazone. Solubility in water, phosphate buffer (pH 7.4), six co-solvent solutions prepared in water as well as phosphate buffer (pH 7.4) and pH-solubility profile of various drugs have been determined at 25°C. Aqueous solubility of various drugs was found to be less than 0.04 mg/mL. Solubility of gliclazide, glipizide and repaglinide increased by 3-6 times by using phosphate buffer (pH 7.4) as solvent. Solubility enhancement by pH modification was not sufficient. Significant enhancement in solubility could be achieved by the use of co-solvents. The combined effect of co-solvent and buffer was synergistic and enormous increase in solubility of sulfonylureas and repaglinide could be achieved. In the case of glitazones, however, co-solvent alone caused significant enhancement; the presence of buffer had negative effect on the solubilization potential of the co-solvents. Up to 763, 316, 153, 524, 297, 792 and 513 times increase in solubility could be achieved in the case of gliclazide, glyburide, glimepiride, glipizide, repaglinide, pioglitazone and rosiglitazone, respectively.     

Microemulsions as potential drug delivery systems: a review

By many estimates, up to 40 percent of new chemical entities discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds. Solubilization of hydrophobic drugs with low aqueous solubility has been a major area of interest in recent years. Various solubilization techniques involve the use of co-solvents and surfactants along with pH adjustments. Applications of microemulsions have also drawn attention in the field of solubilization techniques. Microemulsions are optically isotropic and thermodynamically stable systems consisting of water, oil, a surfactant, and a co-surfactant and are known to enhance the bioavailability of drugs via topical and systemic routes. The objective of this review is to present briefly the possible applications of these novel systems of microemulsions. Most studies reported in the literature have investigated microemulsions intended for dermatological application because of the wider range of potential excipients.     

Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents.

The solubilization behavior of a poorly soluble model drug, phenytoin (PHT), under combined use of surfactants (sodium dodecyl sulfate (SDS), Tween 80) and cosolvents (dimethylacetoamide (DMA), ethanol, poly(ethylene glycol) 400 (PEG), glycerol) was examined. The solubility of PHT in the aqueous surfactant solutions increased linearly with increase of the surfactant concentration. The solubility of PHT in water-cosolvent mixtures roughly followed the log-linear model, which is widely accepted to explain the solubilization behavior of poorly soluble compounds in water-cosolvent mixtures, except for the case of glycerol, in which the solubility was minimal at 10% (w/v) of glycerol. When the cosolvents were added to the aqueous surfactant solutions, their effect on the solubility depended on the combination of the surfactant and the cosolvent. The most striking increase in solubility was observed with DMA, regardless of the type of surfactant. When ethanol was added, an increase in the solubility was observed with the Tween 80 solution, while a dramatic decrease was found with the SDS solution. The addition of glycerol or PEG to the surfactant solutions had only a minor impact on the solubility. These solubilization behaviors of PHT in the surfactant-cosolvent mixtures were partially explained by the solubility model introduced in our previous paper [Kawakami, K., Miyoshi, K., Ida, Y., 2004. Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent. J. Pharm. Sci. 93, 1471-1479]. Addition of the cosolvents to the surfactant solutions generally offered only a small advantage from the viewpoint of improving solubility because of the decrease in the solubilization capacity of the micelles.     

Surfactant solubility and aggregate orientation in hydrofluoroalkanes

PURPOSE: To find surfactants soluble in the two hydrofluoroalkane (HFA) propellants, HFA-134a and HFA-227ea; to compare surfactant solubility in the two propellants with those in 2H,3H-decafluoropentane (DFP) in order to assess latter's suitability as a liquid model propellant and to investigate surfactant aggregation and aggregate orientation in HFAs. METHODS: To assess surfactant solubility, HFA was added to a known amount of surfactant until dissolution was visibly apparent. An iodine solubilization method was used to determine surfactant aggregation behaviour in DFP. Fluorescence spectroscopic investigations on the surfactant orientation in aggregates were carried out in HFAs using a microviscosity sensitive fluorescent probe (1,3-dipyrenylpropane). The aim was to assess viscosity changes in the microenvironment of this lipophilic probe upon incorporation into surfactant aggregates. RESULTS: Soluble surfactants could be found among the polyoxyethylene-ethers and POE-PPO-block copolymer surfactants. Solubility in DFP appears to correlate with solubility in HFA-134a, but not HFA-227ea. Iodine solubilization indicates micellization of Brij 30 in DFP at a cmc (type II association behaviour). L-44 in DFP, on the other hand, does not exhibit a well defined cmc, but shows continuous surfactant aggregation (type I association behaviour). The fluorescence spectroscopic studies showed evidence for probe incorporation into surfactant aggregates in HFAs. CONCLUSIONS: DFP proved to be a good model for HFA-134a only. An L1-aggregate orientation was shown for surfactants in HFAs and is in marked contrast to the chlorofluorocarbon propellant where a L2-aggregate orientation exists.     

Predictive Modeling of Micellar Solubilization by Single and Mixed Nonionic Surfactants

Micellar solubilization is an important concept in the delivery of poorly water-soluble drugs. The rational selection of the type and the amount of surfactant to be incorporated in a formulation require comprehensive solubility studies. These studies are time and material demanding, both of which are scarce, especially during late discovery and early development stages. We hypothesized that, if the solubilization mechanism or molecular interaction is similar, the solubilization capacity ratio (a newly defined parameter) is dictated by micellar structures, independent of drugs. We tested this hypothesis by performing solubility studies using 8 commonly used nonionic surfactants and 17 insoluble compounds with diverse characteristics. The results show a striking constant solubilization capacity ratio among the 8 nonionic surfactants, which allow us to develop predictive solubility models for both single and mixed surfactant systems. The vast majority of the predicted solubility values, using our developed models, fall within 2-fold of the experimentally determined values with high correlation coefficients. As expected, systems involving ionic surfactant sodium dodecyl sulfate, used as a negative control, do not follow this trend. Deviations from the model, observed in this study or envisioned, were discussed. In conclusion, we have established predictive models that are capable of predicting solubility in a wide range of nonionic micellar solutions with only 1 experimental measurement. The application of such a model will significantly reduce resource and greatly enhance drug product development efficiency.     

Study of the solubilization of gliclazide by aqueous micellar solutions

It was of interest to increase the solubility of gliclazide in aqueous media. Therefore, solubilization of gliclazide in a variety of surfactants was investigated. Anionic and cationic surfactants exhibited dramatic solubilizing ability for gliclazide, whereas nonionic surfactants showed significantly lower solubilizing ability. It was found that gliclazide solubility increases with increasing the carbon chain length of cationic surfactants and decreases with increasing the carbon chain length of anionic surfactants. The solubilization data were analyzed on the basis of a pseudo-phase model with gliclazide exhibiting moderate partition coefficients into the micellar phase. The possible sites of solubilization of gliclazide in the micelle were examined by studying the effect of NaCl on solubilization and by comparing the absorption spectra of gliclazide in different solvents. The results obtained from these two experiments indicated that gliclazide is solubilized mainly in the inner core of the cationic surfactant micelles and in the outer regions of the anionic surfactant micelles.     

Micellar Solubilization of Timobesone Acetate in Aqueous and Aqueous Propylene Glycol Solutions of Nonionic Surfactants

The micellar solubilization of timobesone acetate, a novel topical corticosteroid, was studied in aqueous and aqueous propylene glycol solutions of 1 to 5% nonionic surfactants at 25°C. The surfactants used were polyoxyethylene (POE) sorbitan monofatty acid esters (polysorbates), fatty acid esters (Myrj), and fatty alcohol ethers (Brij), as well as sucrose monolaurate (Crodesta SL40). The increase in the solubility of timobesone acetate in the micellar solutions was dependent on the type and concentration of surfactant. The solubilizing capacity of the surfactant micelles and the distribution coefficient of timobesone acetate in aqueous micellar solutions were found (1) to increase with increasing length of the hydrophobic fatty acid group; (2) to increase according to the structure of the hydrophilic group in the order of POE sorbitan ester, sucrose ester, POE ester, and POE ether; (3) to be unaffected by the increase in POE chain length; and (4) to tend to decrease in surfactant containing unsaturated fatty acid groups. In aqueous propylene glycol solution, the solubilizing capacity increased slightly, i.e., up to 1.5-fold in 50% propylene glycol solution, for the ester-type surfactants (polysorbates and Myrj). But this increase was not observed in the ether-type surfactant (Brij) solution. The distribution coefficient decreased logarithmically with increasing concentrations of propylene glycol in the solution. This was caused by the logarithmic increase in the timobesone acetate solubility in the bulk phase, while the solubility in the micellar phase was practically unchanged. The results support the equilibrium distribution model of micellar solubilization.     

Solubilization of water by hydrotropic salts

The effect of some electrolytes, nonelectrolytes, surfactants, and hydrotropic salts on the solubility of water in 1-butanol and 1-hexanol was investigated. While sodium chloride and sodium acetate decrease the solubility of water in 1-butanol, urea has no significant effect. The ionic surfactants, sodium lauryl sulfate and cetrimide, cause an initial decrease in the solubility of water in 1-butanol followed by an increase at high surfactant concentrations. The nonionic surfactant, polysorbate 20, does not show the initial decrease in water solubility. On the other hand, the hydrotropic salts, sodium benzoate, sodium salicylate, and sodium gentisate, are shown to be the best water solubilizers in 1-butanol. Sodium salicylate showed the maximum solubilizing power. The effect of sodium benzoate, sodium salicylate, and sodium lauryl sulfate on the solubility of water in 1-hexanol was also investigated. Similar results were obtained.     

Pineal hormone melatonin: solubilization studies in model aqueous gastrointestinal environments

In view of the variable oral absorption, short biological half-life and extensive first pass metabolism of the pineal hormone melatonin, an investigation of its solubilization profile in modified aqueous media is described. Four readily available surfactants were examined with respect to their ability to enhance the solubility of melatonin under simulated physiological conditions. The most effective surfactant was found to be the sodium salt of dioctyl sulfosuccinate (DSS), which augmented the aqueous solubility of the hormone by 23%. This is attributed to a favourable stereoelectronic interaction between DSS and the nucleus of melatonin, which seems to be independent of the pH of the dissolution medium. A noteworthy synergistic effect in the aqueous solubilization of the hormone occurs when a 1:2 DSS-sodium dodecyl sulphate mixture is used.     

Dissolution kinetics of griseofulvin in sodium dodecylsulphate solutions

The rate-limiting step in the absorption of poorly water-soluble drugs is often the dissolution process of these compounds. Surface-active agents influence the dissolution process by wetting and solubilizing. In order to study the effect of solubilization, a rotating-disk apparatus was used with griseofulvin as a model drug substance and sodium dodecylsulphate (SDS) as a model surfactant. The dissolution kinetics of griseofulvin in SDS solutions could adequately be described by the convective-diffusion model and the phase-separation model for micellar systems. The calculated micellar diffusion coefficient of SDS was in close agreement with values reported in the literature.     

Solubilization of NSC-639829

Solubilization using pH combined with cosolvents, surfactants, and complexants are investigated for NSC-639829, an investigational anti-tumor agent. The intrinsic solubility of the drug is approximately 30 ng/ml and it has an ionizable dimethyl aniline group with an approximate base pK(a) of 5. Samples buffered at pH 1.0, 2.0, and 7.0 with various concentrations of the solubilizing agents were used to study the solubilization of NSC-629829 when present as charged and uncharged species. The solubilization of NSC-639829 was found to be much more effective when the drug was present primarily in ionized form. At pH values 1.0 and 2.0 where the surfactant (SLS) and complexant (SBEbetaCD) carried a negative charge enhanced solubilities of more than a million-fold were observed for the drug.     

The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs

The effects of types of surfactants on the solubilization and dissolution of poorly soluble acidic drugs were compared to identify the most suitable surfactant for conducting an acidic drug dissolution test. Cetyltrimethylammonium bromide (CTAB) as a cationic surfactant, sodium lauryl sulfate (SLS) as an anionic surfactant, and polysorbate 80 as a non-ionic surfactant were used in the study. And, mefenamic acid, nimesulide, and ibuprofen were selected as model drugs. The dissolution rates of these acidic drugs were substantially enhanced in medium containing CTAB. Electrostatic interactions between acidic drugs and cationic surfactants were confirmed by measuring UV spectra of each drug. Solubility of drugs in various media and the partition coefficients of drugs into micelles were found to depend on drug characteristics. For acidic drugs, the ability of media containing a cationic surfactant to discriminate rates of dissolution of acidic drugs seemed to be greater than that of media containing other surfactant types.     

Comparison of impact of the different hydrophilic carriers on the properties of piperazine-containing drug.

The objective of this study was to determine the impact of a series of nonionic surfactants on the solubility of piperazine-containing drug (meclizine, MZ) in comparison to that of natural cyclodextrins (alpha-CD and beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD). The solubility of the drug was studied in either CDs solutions or nonionic surfactant solutions. Three classes of nonionic surfactants were used namely; polyoxyethylene (POE) sorbitan fatty acid esters (polysorbates), POE fatty acid esters (Myrjs) and polyethylene oxide (PEO) fatty alcohol ethers (Brijs and Eumulgins). The solubility of MZ was increased linearly with the increasing surfactant concentration, indicating that micellar solubilization follows the partition model. It was found that the longer the hydrocarbon chain in a homologous series, the more efficient is the solubilizing power of surfactant. For example, polysorbate 80 (Tween-80) is a more efficient solubilizer than polysorbate 20 (Tween-20), indicating that the drug was incorporated in the core of micelle more than the capsular region of the micelle. On the other hand, in case of POE fatty acid esters, the solubilizing power increased with decreasing polyoxyethylene chain as Myrj 53 was more efficient than Myrj 59. In class of PEO fatty alcohol ethers, the shorter the hydrophilic chain and longer lipophilic chain, the more efficient was the solubilizing capacity. Thus, Brij 58 was more efficient solubilizer than Brij 35 and Eumulgin C1000 was more active than Eumulgin C1500. Comparatively, Eumulgin C1000 had the highest solubilizing power for MZ among the studied PEO fatty alcohol ethers and other groups of surfactants. The solubility action of surfactants toward MZ was increased by raising the temperature of the surfactant solutions from 30 to 45 degrees C. Hydrophilic macromolecules (PEG 1000 and PEG 6000) or cosolvents (glycerol and propylene glycol) have a very slight effect on the solubility of MZ and confirm the predominance of hydrophobic interaction between the drug and nonionic surfactants. A(L)-type phase solubility diagrams were obtained for the drug with alpha-, beta- and DM-beta-CDs showing that the solubility of MZ was enhanced through inclusion complexation. Comparatively, DM-beta-CD had the highest solubilizing efficiency for the drug among the investigated CDs, which could be attributed to its larger hydrophobic cavity size.     

萘普生溶解性能的研究

本文对萘普生在不同碱性药物的溶液中的溶解性能和稳定性以及在不同溶媒和复合溶媒的溶解性能进行了初步的研究。绘制了萘普生在聚乙二醇_(400)、乙醇、水系统和在二甲基亚砜、PEG400、水系统中的助溶相图,对选择合理的复合溶媒配比,了解溶液的可稀释程度具有一定的指导意义。选择适当配比的上述两种复合溶媒,其溶解量均在50mg/ml以上。     

The solubility-permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on surfactant concentration (C(S)). The analysis reveals that (1) the effective UWL thickness (h(aq)) quickly decreases with increasing C(S) above the critical micelle concentration (CMC), such that P(aq) markedly increases with increasing C(S); (2) the free fraction of drug available for membrane permeation decreases with increasing C(S) above CMC, such that P(m) decreases with increasing C(S); and (3) P(aq) increases and P(m) decreases with increasing C(S) above CMC, consequently the UWL is effectively shorted out and the overall P(eff) tends toward membrane control with increasing C(S). The model enabled excellent quantitative prediction of the progesterone P(eff) as a function of C(S) in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.     

The Effect of Some Ionized and Neutral Surfactants and Bile Acids upon Sodium and Water Transport from Tied Jejunal Loops in Anaesthetized Rats

Abstract: Surfactants of diverse types, viz. dioctylsulphosuccinate, cetrimonium bromide, benzalkonium chloride, Lubrol$rG WX, Triton$rG X100, desoxicholic acid, cholic acid and glycodesoxicholic acid all affected jejunal transport of sodium and water in the same way as previously shown for dodecylsulphate: From hypotonic sodium chloride solutions, they inhibited net water absorption or induced secretion in a dose dependent manner; from hypertonic sodium salt solutions net sodium absorption was enhanced. The results indicate that, with increasing doses of surfactant, diffusion becomes increasingly important as the determinant of net sodium transport, suggesting that the surfactants cause increased passive permeability of the intestinal epithelium. Taurodesoxicholic acid caused inhibition when tested with hypotonic saline, and by analogy is assumed to act in the same way as the above mentioned surfactants. Some of the non-ionic surfactants tested did not influence jejunal transport.     

Impact of Surfactant and Surfactant-Polymer Interaction on Desupersaturation of Clotrimazole

The impact of surfactants on supersaturation of clotrimazole solutions was systematically evaluated. Four clinically relevant surfactants, sodium dodecyl sulfate, vitamin E TPGS, Tween 80, and docusate sodium were studied. The induction time for nucleation and rate of desupersaturation were determined at a supersaturation ratio of 90% amorphous solubility. Measurement was also performed in the presence of predissolved hydroxypropyl methylcellulose acetate succinate to study the effect of surfactant-polymer interaction on desupersaturation. The 4 surfactants showed varied effects on desupersaturation. From supersaturation maintenance perspective, in the presence of hydroxypropyl methylcellulose acetate succinate, the rank order for the 4 surfactants was found to be: docusate sodium > vitamin E TPGS > sodium dodecyl sulfate > Tween 80. Given the importance of maintaining supersaturation and varied effect of surfactants on nucleation kinetics and desupersaturation rate, a careful examination of active pharmaceutical ingredient, polymer and surfactant interaction on an individual basis is recommended for selecting an appropriate surfactant for use in amorphous solid dispersion formulation.     

Co-solubilization of poorly soluble drugs by micellization and complexation

The use of combined approach of surfactants and cyclodextrins in solubilization of poorly soluble drugs has been described in literature. In this report, a mathematical model has been developed to provide the quantitative basis for this approach. First, by way of hypothetical examples and simulations, the influence of various interaction parameters on the phase solubility profile is presented. Additionally, the model results are compared with (a) results reported by Yang et al., with NSC-639829, sodium lauryl sulfate (SLS) and sulfobutyl-ether-beta-cyclodextrin ((SBE)(7M)-beta-CD) and (b) solubility of methylprednisolone, a model poorly soluble drug, in the presence of its water-soluble 'surfactant-like' prodrug, methylprednisolone 21-hemisuccinate, and (SBE)(7M)-beta-CD. The model shows good agreement with experimental data. Furthermore, theoretical simulations show that the combined solubility is less than the sum of the individual solubility values in cyclodextrins and surfactants. Based on the hypothetical case and the two examples, the factors affecting the phase solubility profile in mixed solutions of surfactants and cyclodextrins are presented. Finally, the limitations of the model to explain co-solubilization by surfactants and cyclodextrins are discussed.     

Bilayer to micelle transition of DMPC and alcohol ethoxylate surfactants as studied by isoperibol calorimetry

The interaction of dimyristoylphosphatidylcholine (DMPC) with non-ionic surfactants has been studied using isoperibol calorimetry. Phospholipid-surfactant systems were formed in the isoperibol calorimeter with varying amounts of surfactant and the change in enthalpy on formation was measured. Solubilization of the phospholipid lamellae was assessed as a decrease in the enthalpy of reaction of co-films containing DMPC and increasing amounts of three linear alcohol ethoxylate surfactants: C(10)H(21)(OCH(2)CH(2))(3)OH, C(10)H(21)(OCH(2)CH(2))(5)OH, or C(12)H(25)(OCH(2)CH(2))(7)OH. The isoperibol calorimetry data for DMPC/surfactant/water systems were consistent with a theoretical three-stage model for the solubilization of phospholipids by surfactants, whereby phospholipid bilayers are transformed into mixed micelles with increasing amounts of surfactant. The results indicate that: (i) the interaction between phospholipid and surfactants results in a non-linear correlation between the enthalpy of reaction and the surfactant concentration; (ii) the structural stage of the lamellar to micelle transition (mixed bilayers, mixed micelles, or both) can be determined from calorimetric data; (iii) phase boundaries in the solubilization process (bilayer saturation, micelle saturation) can be identified as break points in the enthalpy-concentration curve; and (iv) increasing the hydrophilicity of the surfactant results in a decrease of the surfactant concentration producing the onset of solubilization.