Co-solvent systems

Supercritical fluid extraction — During the past two decades, important progress was registered in the extraction of bioactive phytochemicals from plant or food matrices. Most of the work in this area focused on non-polar compounds (terpenoid flavors, hydrocarbons, carotenes) where a supercritical (SFE) method with CO2 offered high extraction efficiencies. Co-solvent systems combining CO2 with one or more modifiers extended the utility of the SFE-CO2 system to polar and even ionic compounds, e.g., supercritical water to extract polar compounds. This last technique claims the additional advantage of combining extraction and destruction of contaminants via the supercritical water oxidation process."... 

During the past 30 years, there have been significant developments of parenteral disperse formulations. The use of parenteral emulsions can overcome the problems of low aqueous solubility and water hydrolysis of many drugs [184, 185]. Such formulations can avoid the use of conventional co-solvent systems and the undesirable effects caused by precipitation of drugs at the injection site. Recent developments of parenteral disperse formulations have the potential to provide sustained release and targeting of drugs [186-189],... 

It the productivity target cannot be achieved then a co-solvent system could be selected using solubility prediction methods like NRTL-SAC [1] and Local UNIFAC [4], The addition of a second solvent to increase solubility is an effective way of increasing productivity for a sparingly soluble solute. 

Both the Hildebrand and MGSA theory can be applied to co-solvent systems by modifying the interaction parameters. 

Even though Hildebrand theory should not apply to solvent systems having considerable solvent-solvent or solute-solvent interactions, the solubility of compounds in co-solvent systems have been found to correlate with the Hildebrand parameter and dielectric constant of the solvent mixture. Often the solubility exhibits a maximum when plotting the solubility versus either the mixed solvent Hildebrand parameter or the solvent dielectric constant. When comparing different solvent systems of similar solvents, such as a series of alcohols and water, the maximum solubility occurs at approximately the same dielectric constant or Hildebrand parameter. This does not mean that the solubilities exhibit the same maximum solubility. 

Corrigan, O.l. (1991). Co-solvent systems in dissolution testing theoretical considerSiimip,Dev. Ind. 

Megrab, N.A., A.C. Williams, and B.W. Barry. 1995. Oestradiol permeation across human skin, silastic and snakeskin membranes The effects of ethanol/water co-solvent systems. Int J Pharm 116 101. 

In the polymer industry involving SCFs, a co-solvent is commonly needed because the solubility of a polymer in high-pressure is very low. In order to consider an effective method for the production of polymeric materials using scC02, it is essential to understand the liquid-liquid (L-L) phase behavior of C02 + polymer + co-solvent systems at constant pressure and temperature [9, 20]. 

Since the basic moduls as well as these process enhancements are standardized it is easy to prepare a unit for the RETROFIT of additional options like co-solvent systems, additional inbtermediate separators, columns, extractors... 

Water-in-oil gel emulsions were tested in enzymatic aldolization of selected N-Cbz-amino aldehydes (Figure 19.3), N-Cbz-3-amino propanal (4), N-Cbz-glycinal, (5), (S)-N-Cbz-alaninal (6), and (R)-N-Cbz-alaninal (7) catalyzed by RAMA and L-rham-nulose-1-phosphate aldolase (RhuA) and L-fuculose-1-phosphate aldolase (FucA) from Escherichia coU [27,28]. The largest differences between conventional dimethyl formamide (DMF)/water co-solvent systems and gel emulsions were observed with RAMA and FucA catalysts (Figure 19.3). The emulsion media enhanced the catalytic efficiency of RAMA towards the N-Cbz amino aldehydes tested three, five. 

Gould, P.L., Goodman, M., Hanson, P.A., 1984. Investigation of the solubility relationships of polar, semi-polar and non-polar drugs in mixed co-solvent systems. Int. J. Pharm. 19, 149-159. 

A typical solvent or co-solvent system is selected based on the ability to solvate the analyte(s) relative to the undesired matrix components and the ease with which the solvent can be eliminated after extraction. Co-solvent blends are useful because the polarity (or other properties) can be tailored to that of the analyte(s). Traditional aprotic organic solvents are useful because they can be removed quickly and at low temperatures. Because of the dramatic increase in extraction efficiencies, solvents that have only moderate extraction properties at room temperature and atmospheric pressure can perform quite well under ASE conditions. Because organic-aqueous co-solvents can be used, it is often possible to prepare a solvent that can chemically neutralize the analyte molecule, thereby further facilitating the extraction. Dilute organic acids or bases can be employed for this purpose. Strong mineral acids are generally undesirable because they attack and destroy the stainless steel bombs or other instrument system components. 

H. Matsuda, K. Kaburagi, K. Kurihara, K. Tochigi, K. Tomono. Prediction of solubilities of pharmaceutical compounds in water + co-solvent systems using an activity coefficient model. Fluid Phase Equilibria 290 (2010) 153-157. 

Centrifugation or ultracentrifugation may be preferable for certain samples that are difficult to filter. Solubility samples in co-solvent systems with high viscosity are such examples. If the solute is less dense than the solubility medium, it will float on the surface, making it difficult to sample the solution. This may be particularly problematic for compounds with low solubility where a single particle carried over to the solution may cause significant overestimation of the true solubility. 

Special precautions are required when determining solubility in non-aqueous solvents. Since many non-aqueous systems are viscous, it may be more practical to use weight (W/W) instead of volume (W/V) to represent solubility. Since not all biters are compatible with non-aqueous solvents, it is essential to choose the correct type of biter. Upon dilution of the saturated solution for analysis, it is important to ensure that the compound does not precipitate. Precipitation may occur in many co-solvent systems because the solubility changes that accompany dilution are log-linear. 

This chapter reviews a) the characterization of proteins and peptides in a variety of non-aqueous or co-solvent conditions, both acceptable and unacceptable for pharmaceutical applications, b) the applicability of non-aqueous conditions for increasing solubility, stability and activity, and c) novel drug delivery and formulation process technology applications. This review focuses on non-aqueous solutions, suspensions and co-solvent systems that result in miscible conditions. 

Bovine serum albumin (BSA) and lysozyme solubility are well documented in organic solvents, some of which are pharmaceutically acceptable (Table 3) (Houen, 1996). In general, good BSA solubility was observed in glycerol and dimethyl sulfoxide (DMSO), while poor solubility was observed in several alcohols. The solubility of lysozyme (pH 6.0) in 34 solvents and co-solvent systems was also characterized (Table 3) (Chin et ah, 1994). To add complication, the solubility of lysozyme was difficult to measure, because solutions above 10 mg/ml lysozyme formed viscous gels. The protein solubility was then correlated with the characteristics previously outlined. 

It should be mentioned that crystal structure data are often obtained from co-solvent systems (Desai and Klibanov, 1995). For example, crystals of ubiqui-tin, papain and a heptapeptide were grown from 30% polyethylene glycol (PEG) 4000, 62% MeOH and a DMSO/isopropanol mixture, respectively (Kamphius et al., 1984 Karle et al., 1993 Love et al., 1997). The orthogonal and tetratogonal crystal forms of cyclosporine were prepared from 25% PEG 300 and acetone, respectively (Petcher et al., 1976 Kessler et al., 1985 Loosli et al., 1985 Verheyden et al., 1994a). Furthermore, cyclosporine and leuprolide form thermotropic liquid crystals when dried from EtOH and lyotropic liquid crystals when solubilized in PG, respectively (Tan et al., 1998 Lechuga-Ballesteros et al., 2003 Stevenson et al., 2003). 

The selection of a vehicle can dramatically affect delivery and consequently efficacy of topical preparations. In terms of transdermal delivery, where delivering therapeutic agents for systemic effects is desired, solvents and co-solvent systems are widely used to improve both the amount and range of drugs that can be administered at therapeutic levels through the skin. Vehicles used in transdermal systems, such as patches, have recently been reviewed (Williams, 2003). In contrast, the focus of this chapter is on the use of solvents in topical dosage forms, i.e. preparations intended for a local or regional effect on the skin. 

Solubility of the drug substance and other critical excipients in water and co-solvent systems... 

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