Cosolvency of Dimethyl Isosorbide for Steroid Solubility

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI–PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.     

Gastroretentive Cosolvent-Based In Situ Gel as a Promising Approach for Simultaneous Extended Delivery and Enhanced Bioavailability of Mitiglinide Calcium

Ion cross-linking in situ gels are novel liquid sustained-release drug delivery systems. These systems are unsuitable for poorly water-soluble drugs such as the novel antidiabetic drug mitiglinide calcium (MTG). Thus, our goal was to assess the possibility of using cosolvency approach in formulating gastroretentive in situ gel of the short half-life MTG to simultaneously enhance its bioavailability and sustain its release. MTG in situ gel formulations were developed using propylene glycol as a cosolvent to dissolve MTG in the polymer solution, followed by characterization of viscosity, gel strength, floating ability, and in vitro MTG release and phramacokinetics evaluation. The optimized formulation (composition: 1% gellan gum, 0.75% sodium alginate, 0.75% calcium carbonate, and 7.5% propylene glycol) exhibited reasonable viscosity but on introduction into simulated gastric fluid, it formed firm gel that floated within seconds over the surface and remained buoyant for 24 h. The formula exhibited in vivo sustained release manner of MTG over 24 h and improved the bioavailability of the drug. Thus, cosolvency presents a promising approach to deliver hydrophobic drugs in sustained-release liquid formulations. These formulations will improve diabetic patients' compliance by eliminating the necessity of frequent dosing with a better disease management.     

Cosolvency and Cosolvent Polarity

The solubilities of three poorly soluble drugs, phenytoin, benzocaine, and diazepam, in cosolvent– water mixtures have been previously shown to be approximated by the log-linear solubility equation; log (S _m/S _w) = f, where S _m and S _w represent the solubilities of the drug in the solvent mixture and water, respectively, f is the volume fraction of cosolvent, and is the slope of a plot of log (S _m/S _w) vs f. In this study, the slopes, , of the solubility plots were related to indexes of cosolvent polarity including the dielectric constant, solubility parameter, surface tension, interfacial tension, and octanol–water partition coefficient. Those polarity indexes that reflect the cohesive properties of the solvents such as the solubility parameter and interfacial tension resulted in the highest correlations with the slope, . The hydrogen bonding ability of the neat cosolvent, expressed as the density of proton donating groups (HBD) or acceptor groups (HBA), was also found to be highly correlated with . Additional relationships derived from theories involving solubility parameters and interfacial tension provide improved correlations between the cosolvent polarity and . These results and analysis provide the basis for the estimation from physicochemical parameters of the appropriate type and amount of cosolvent needed to solubilize nonpolar drugs.     

Cosolvency and Deviations from Log-Linear Solubilization

The solubilities of three nonpolar drugs, phenytoin, diazepam, and benzocaine, have been measured in 14 cosolvent–water binary mixtures. The observed solubilities were examined for deviations from solubilities calculated by the equation log S _m = f log S _c + (1 – f) log S _w, where S _m is the solubility of the drug in the cosolvent–water mixture, S _c is the solubility of the drug in neat cosolvent, f is the volume fraction of cosolvent, and S _w is the solubility of the drug in water. When presented graphically, the patterns of the deviations were similar for all three drugs in mixtures of amphiprotic cosolvents (glycols, polyols, and alcohols) and water as well as nonpolar, aprotic cosolvents (dioxane, triglyme, dimethyl isosorbide) and water. The deviations were positive for phenytoin and benzocaine but negative for diazepam in mixtures of dipolar, aprotic cosolvents (dimethylsulfoxide, dimethylformamide, and dimethylacetarnide) and water. The source of the deviations could not consistently be attributed to physical properties of the cosolvent–water mixtures or to alterations in the solute crystal. Similarities between the results of this study and those of previous investigations suggest that changes in the structure of the solvent play a role in the deviations from the expected solubilities.     

Preparation and Characterization of Acetoacetoxyethyl Methacrylate‐Based Gels

Novel polymeric gels have been prepared by radical copolymerization of acetoacetoxyethyl methacrylate (AAEM) and hydroxyethyl methacrylate (HEMA) in water‐ethanol medium. The influence of the HEMA:AAEM ratio and crosslinker concentration on properties of gels was studied. Independently on gel composition the maximum swelling was detected in chloroform. It was found that PAAEM gels possess phase transition temperature or upper critical solution temperature (UCST) in alcohol‐water solutions. UCST decreases in linear order from 75 to 10 °C when HEMA content in gel structure increases. The minimal UCST of AAEM/HEMA gels in binary alcohol‐water mixtures is shifted toward lower temperatures and lower alcohol concentrations when the alkyl chain of alcohol increases.

AAEM/HEMA gels prepared at different BIS concentrations (1:1 mol‐%, 2:2.5 mol‐%, 3:5 mol‐%).     

氯诺昔康注射剂的研制——处方前溶解度研究

目的为难溶性非甾体抗炎药氯诺昔康注射剂的制备进行处方前溶解度研究。方法采用高效液相色谱法测定氯诺昔康在溶液中的溶解度。研究了pH值、潜溶剂、胶束形成及环糊精包合作用对氯诺昔康溶解度的作用。结果氯诺昔康的溶解度ST随着pH值的升高而呈指数规律增加,与表面活性剂浓度Csurf和羟丙基β环糊精(HPβCD)浓度呈线性关系;logST与三种潜溶剂分数fc间具有良好的线性关系(r>0.98)。结论常用可注射表面活性剂和潜溶剂对氯诺昔康的溶解度提高作用不显著,通过控制pH值和使用HPβCD包合,可使氯诺昔康在水溶液中的溶解度达到注射液的浓度要求。     

葫芦素E溶解度、正辛醇-水及脂质体-水分配系数测定

目的测定葫芦素E溶解度、正辛醇-水分配系数及脂质体-水分配系数。方法分别采用平衡法、经典摇瓶法及平衡透析法测定葫芦素E溶解度、正辛醇-水分配系数及脂质体-水分配系数。结果葫芦素E在水中溶解度为0.155 mg.L-1,在乙醇、叔丁醇中有潜溶现象;正辛醇-水分配系数为(2.088±0.054);脂质体-水分配系数为0.003~1.819。结论葫芦素E为水不溶性药物;正辛醇-水分配系数及脂质体-水分配系数均中等偏低。