Theoretical and practical considerations when selecting solvents for

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Applied Chemistry

Theoretical and practical considerations when selecting solvents for use in extractables studies of polymeric contact materials in single-use systems applied in the production of biopharmaceuticals Samuel Dorey, Ina Pahl, Isabelle Uettwiller, Paul Priebe, and Armin Hauk Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b04940 • Publication Date (Web): 27 Apr 2018 Downloaded from http://pubs.acs.org on April 28, 2018

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Industrial & Engineering Chemistry Research

Theoretical and practical considerations when selecting solvents for use in extractables studies of polymeric contact materials in single-use systems applied in the production of biopharmaceuticals

Samuel Doreya,*, Ina Pahlb, Isabelle Uettwillera, Paul Priebe c, Armin Haukb a

Sartorius Stedim FMT S.A.S., avenue de Jouques, CS91051, ZI des Paluds, 13781 Aubagne Cedex, France

b

Sartorius Stedim Biotech GmbH, August Spindler Straße 11, 37079 Göttingen, Germany

c

Sartorius Stedim Biotech, Johnson avenue, Bohemia, NY, USA

* Corresponding author: Samuel Dorey, [email protected]

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Abstract

Regulatory authorities require the biopharmaceutical industry to demonstrate that extractables that may migrate from production systems do not alter the safety, efficacy, potency or purity of drug products. Extractables studies of polymeric materials used in production systems and in particular single-use systems (SUS) are designed to show material safety and should support the users to perform risk-based toxicological assessment of leachables that could potentially enter into the final product under process conditions. In this paper, we intend to improve the understanding of solvent-polymer interactions and thereby allow the prediction of extractables from a range of fluids based on their chemical properties for the fluids. The possibility to predict solvent-polymer interactions and polymer swelling in biopharmaceutical applications based on solubility parameters will be introduced. Keywords: extractables; solvent selection; polymer solubility parameters; partition coefficient and pH effect; gamma-irradiation; multilayer films;

2

Introduction

Regulatory authorities require the biopharmaceutical industry to demonstrate that extractables that may migrate from production systems into process streams do not alter the safety, efficacy, potency or purity of drug products1–3. In pharmaceutical applications it is a legal requirement to demonstrate the suitability of a contact material for its intended use4 in contrast to the food industry where standardized extraction conditions are defined by regulatory authorities in guidelines (FDA Guidance to Industry5) and/or regulations6, for extractables studies. Considering, an “intended use” can be associated with very different

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use-conditions, it is justifiable, that extractables-studies for pharmaceutical contact materials are conducted under quite different conditions. To allow a reasonable material-qualification and risk assessment, in extraction studies, commonly used solvents have a “stronger” propensity to extract chemicals from plastics than the pharmaceutical contact liquid can do. Extraction studies are conducted under “worst-case” conditions at elevated temperature and high material/solvent ratios2,3,7,8. Consequently pragmatic protocols have been established to link extraction conditions in extractables studies with process conditions2,3,7,8. These approaches, although in line with the expectations from authorities, more or less ignore the underlying physical and chemical interactions. In this paper, we intend to improve the understanding of solvent-polymer interactions and thereby allow the prediction of extractables from a range of fluids based on the chemical properties of the fluids. Using the underlying chemical properties of the solvents and plastics allows for the use of a small panel of solvents that mimic the extraction behavior of a range of process solutions. The task of selecting a solvent or solvent mixture with a desirable combination of physical properties, to meet the needs of specific applications, has largely been tackled using a combination of heuristics and experimental studies9–12. Models have been proposed to make use of the different existing predictive polymer miscibility concepts in performing a computer aided molecular design, thereby transferring the solvent search from the laboratory to the desktop13–23. However, in this context of solvent selection, we would like to highlight it was not our intention to use computer aided molecular design, because we consider our selection not as completely unlimited. There is considerable guidances existing from industry and regulatory bodies in the food-contact and pharmaceutical area. The objective of an extractables study is the chemical characterization of the plastic parts made out of polyethylene, polypropylene, polyethylene-vinyl acetate, polyethylene terephthalate, polyethersulfone and cellulose acetate used in food and biopharmaceutical industry. The different compounds which can be found during extractions from polyolefin based polymers extracts are oligomers, additives and additive derivatives, ketones, aldehydes, esters ,etc.24. With our experiments, we will focus on the solvent effect, which means the partition of an extractable between the solid and the liquid phase under equilibrium conditions. Based on the general extractables study requirement to represent “worst case”, we consider equilibrium conditions as relevant, because they represent the maximum achievable concentration in a given materialsolvent system2,3 without physical changes and without functional property loss within the contacted material. In the following study, we will not focus on kinetic aspects of extractables release; comprehensive methodologies, studies and reviews including kinetic aspects can be found extensively elsewhere25–28. The aim of this study is to provide a scientific based and pragmatic approach for solvent selection to conduct extractable studies while considering in parallel various initiatives in industry organizations (BPSA, PDA, BPOG, PQRI, ASME BPE)29–32, standards organizations and regulatory authorities (USP, ASTM, EU Directive, UK Statutory Instrument, FDA)5,6,33–35. Current practice is that alcohols like ethanol and isopropanol and their mixtures with water are preferred solvents to bracket biopharmaceutical and food applications. Also, there are proposals in the pharmaceutical area with water-ethanol mixtures acidic and alkaline solutions5,6,31–35. Industry organizations, standards organizations and regulatory authorities thus proposed solutions to cover independently several steps of the biopharmaceutical applications. Our aim is to identify extraction solutions which can cover the entire biopharmaceutical process and which can support the biopharmaceutical


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industry and the needs of the supplier industry. The selection of solvents we propose, is based on both the physical-chemical parameters of the solvents found in literature information and practical aspects. Selection criteria that were considered include the use of extractants that will extract unique compounds, those that require little effort for sample preparation/ sample manipulation, use-solvents with the least impact on results from analytical tool, the use of solvents that are most applicable to a range of analytical tools, and the use of solvent bracketing process media in biopharmaceutical applications. In addition to theoretical considerations, we will present results from recent extractables experiments demonstrating the influence of several solvents on extractables data.

3

Materials and Methods

We took representative plastics and exposed them to a possible range of extraction solvents, then analysed the extracts by following analytical methods. 3.1

PE film, EVA film, tubing and cartridges

The structure of the multilayer film samples are depicted in Figure 1. The PET film is composed sequentially of polyethylene (PE), ethylene vinyl alcohol (EVOH), polyamide (PA) and polyethylene-terephthalate (PET) and has a thickness of approximately 200 µm. The EVA film is composed of ethylene vinyl acetate (EVA) and EVOH, and has a thickness of approximatively 360 µm. The PE film is composed sequentially of polyethylene (PE), ethylene vinyl alcohol (EVOH), and polyethylene (PE) with a thickness of around 400 µm. TPE tubing is a mono material of TPE with a hardness shore A of 50-60. Silicone tubing is a mono material of Si(Pt) with a hardness of 50-60 shore A. Both tubing have dimensions have an internal diameter of 13 mm and an outer diameter of19 mm (ID-OD).

PE film :

PET film :


3


OH

Backbone

p EVOH

m

O

Contact layer

O x

y EVA

EVA film:

Figure 1: Structure of PE film (top), PET film (middle) and EVA film (bottom)

The construction scheme of a filter cartridge and a filter capsule are shown in Figure 2 and Figure 3. In the cartridge, the outer cage, inner cage, end caps, adapters are made out of polypropylene. The filter media can be prepared with single / multi-layer membrane, made of either PES (Polyethersulfone), or CA (Cellulose Acetate), or ePTFE (exp. Polytetrafluorethylene), or PP (Polypropylene), or non-woven filter made of PP. The support media can be made out of PP or PET. The filter capsule is made out of a filter cartridge and a polypropylene housing.

Figure 2: Scheme of a filter cartridge

Figure 3: Scheme of a filter capsule 3.2

γ-irradiation


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Bag chambers of PE film, PET film and EVA film are packed and wrapped in specific packaging (PE) and gamma irradiated at room temperature in a 60Co γ-source. All samples have been irradiated at 50±1 kGy. The first analysis was performed on the film samples approximatively 5 days after γ-irradiation. Capsules were γirradiated at 50 kGY±2 kGy. 3.3

Extraction

1st extraction series Extractions were performed with thirteen different solutions for one year under accelerated conditions (per ASTM F1980-99, i.e. 112 days at 40°C with Q10=2). These were 3M NaOH, 1M HCl, 20x DPBS, 20% Ethanol, 8M Guanidine, pure water, pure ethanol, 10% DMSO, 1% Polysorbate 80, 4M NaCl, 1M HCl, 1M NaOH and 4M (NH4)2SO4. Solvents were stored in bags made of either the EVA film with a volume to surface ratio of 1.5-1.8 cm²/mL or with the PE film with a volume to surface ratio of 1.5-1.9 cm²/mL. The 20x DPBS (Modified Dulbecco's phosphate-buffered saline) is a mixture of different salts : 8 mM sodium phosphate, 2 mM potassium phosphate, 0.14M NaCl, 10 mM KCl, pH 7.4, when diluted to 1X with water. 2nd extraction series: Different ethanol concentrations from 0% to 100% were evaluated with pure water as co-solvent. Extractions were performed for 4 days at 40°C in bag chambers made of either the EVA film with a volume to surface ratio of 1.8 cm²/mL or with the PE film with a volume to surface ratio of 1.9 cm²/mL. TPE tubing and silicone tubing were immerged for 4 days at 40°C in the solutions with the different ethanol content with a ratio of ~1.5 cm²/mL. 3.4

Analysis

The applied analytical methods presented herein are standard methods widely used as described in literature2,8. The analytical capabilities are out of scope of this paper. GC-MS/FID Ethanol samples were injected directly in GC. The aqueous extracts were extracted into dichloromethane (DCM) with Cyclohexanon-2,2,6,6-d4 as an internal standard at neutral, low and high pH prior to GC-MS/FID analysis. The DCM extract can be subsequently concentrated prior to GC-MS|FID analysis. Results are expressed in neat concentration. 1 μL of DCM is injected into the GC-MS|FID. An internal standard, 2-fluoro 1,1’-Biphenyl, or Toluene-d8 was added to each sample prior analysis to facilitate quantitative estimation of potential extractable. The extractables present in the extract are identified via a best fit analysis of the mass spectrum to the NIST reference library of mass spectra. Each solution was injected in GC-MS/FID (Agilent Mass Selective Detector and Flame Ionization Detector) equipped with column (DB-5MS, 60m x 0.25mm x 0.25µm). The reporting limit of GC-MS/FID is 0.05 µg/mL. Headspace-GC-MS/FID


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Pure water samples were analysed by Headspace-GC-MS/FID and were spiked with a 10 μg/mL solution of Toluene-d8 as internal standard to facilitate quantitative estimation of potential extractable. The headspace vial was heated at 80°C and the headspace content subsequently transferred to the GC-MS|FID for analysis and identification. Each aqueous extract was analyzed in HS-GC-MS/FID (Perkin Elmer Clarus 680 with Mass Spectrometer Perkin Elmer Clarus 600 T and Auto-Ignite FID Assembly Perkin Elmer) equipped with the headpace (Perkin Elmer Turbomatrix 16) and with a column (Elite 5MS, 60m x 0.25mm x 0.25µm). The reporting limit of Headspace-GC-MS/FID is 0.01µg/mL. HPLC-UV-MS The HPLC-UV-MS method utilizes a reversed phase column (C18) with a gradient mobile phase of acetonitrile and 10 mM ammonium acetate in water and a UV-Vis Diode Array Detector (DAD), and a single-quadrupole mass spectrometer (Agilent UV/Vis Diode Array Detector, Wavelength 220 nm). Samples with 80% Ethanol, 10% DMSO, Pure ethanol, Pure water have been injected directly. Samples with 1M NaOH, 1M HCl, 4M (NH4)2SO4, 4M NaCl, 1% polysorbate 80 were transferred in organic phase through SPE. In addition, external standards of potential extractables of high toxicity concern were analyzed directly in each run. To gain into reliability and to avoid solvent/matrix effect, several potential extractables were monitored for detection using the extracted ion mode with the MS detector. The list given in Table 1 SI includes antioxidants given in the European Pharmacopoeia and which can be expected in extracts from bags. The reporting limit is 0.05µg/mL for all compounds unless specified later on. It is 0.5 µg/mL for the BPA, for the 2,4,8,10Tetraoxa-3,9-diphosphaspiro(5.5)undecane,3,9-bis(octadecyloxy)-, and for the BHT. It is 6 µg/mL for the 2,6di-t-butyl-1,4-benzoquinone. Appropriate and reproducible analytical methods were elaborated to track the target compounds even at the trace level if necessary. ICP-MS The 80% ethanol, 1 M NaOH, 1 M HCl, 1% Polysorbate, 10% DMSO, pure ethanol, and pure water samples were analyzed by ICP-MS after appropriate sample preparation. The 1 M NaOH samples were not analyzed for the presence of sodium since it is in the sample matrix. The elements were analyzed with Agilent 7500 Mass Selective Detector and with a reporting limit of 0.05 µg/mL except for the silicon at 1 µg/mL. the following elements have been monitored: Aluminum, Antimony, Arsenic, Barium, Bismuth, Boron, Cadmium, Calcium, Chromium, Cobalt, Copper, Iron, Lead, Lithium, Magnesium, Manganese, Molybdenum, Nickel, Phosphorus, Platinum, Potassium, Silicon, Silver, Sodium, Strontium, Tin, Titanium, Vanadium, Zinc Ion chromatography (IC) Ion chromatography (IC) has been performed with ICS5000, Thermo Scientific apparatus. Each acid listed in Table 2 SI has been monitored. An AS15 capillary column has been used to track ethanoic acid, 2hydroxypropanoic acid, maleic acid, hexanoic acid, and all other acids listed has been tracked with an AS19 4mm column. A gradient of potassium hydroxide has been used. The detection was achieved by a


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conductivity detector. The reporting limit is 0.05 µg/mL in pure water. The reporting limit is 0.1 µg/mL with the ethanol extracts.

4

Theoretical considerations

We have chosen the following criteria for selecting suitable solvents for extractables experiments: a) The solvent should dissolve typical extractables without any solubility limitations. Low partition coefficients of extractables between polymer and solvent are preferable, the solvents should not destroy the polymers, they should allow acidic and alkaline interactions, and they may increase the solubilisation of extractables in water, such as salt containing solutions36. b) The solvent should fulfill some practical requirements such as providing a boiling point above 40°C and being easily applicable to the analytical methods. In order to conduct extractables studies under accelerating conditions, the extraction needs to be performed at 40°C or higher temperatures depending on the biopharmaceutical process and the material properties. Solvents with a boiling point below or close to 40°C cannot be used due to experimental (solvent loss) and safety reasons. 4.1

Solubility of extractables

Extraction is the process by which compounds from a solid phase where it is known that the system is not in equilibrium enter a liquid. The first requirement to select extraction solvent is to know how compounds will partition between the polymer phase and the liquid phase. We want the dissolution to be a process that does not involve a chemical reaction. 4.1.1

Solvent interactions with small organic compounds

The way how organic compounds interact with solvents is well understood and can be summarized as follows. The interaction between solvent and dissolving compound can be described by the adage “like dissolves like”. Polar molecules dissolve in polar solvents and non-polar molecules in non-polar solvents. Most organic molecules are relatively non-polar and are usually soluble in organic solvents (e.g. diethyl ether, dichloromethane, etc.) but not in polar solvents like water. The polarity of the solvent is related to the dielectric constant of the solvent37,38. The dielectric constant is the measure of the ability of the solvent to separate ionic charges37. Dielectric constants are not the only measure of polarity39–41, which are not useful to apprehend the solutes/solvent interactions in that paper. Protic solvents42, for example water, solvate anions (negatively charged solutes) strongly via hydrogen bonding. Aprotic solvents tend to have large dipole moments43 and solvate positively charged species via their negative dipole. Acetone and Dimethylsulfoxide are aprotic solvents. Finally, common solvents may be separated into different classes44 and the properties of some solvents are listed in Figure 1 SI. Regarding organic compounds, the dielectric constant correlates with molecular weight44. The dielectric constants of esters are well below those of alcohols (33-10 respectively in the 30-130 Da range) and ketones (20-13 respectively in the 60-110 Da range)38. Detailed tables of polarity can be found elsewhere38.


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The strong polarity of water is indicated, at 25 °C, by a dielectric constant of 78,345. Water cannot be therefore considered as a good solvent for polymers and their oligomers. We expect that long hydrocarbons and long carboxylic acids cannot be dissolved into water. There is a need to increase the polar properties of long organic compounds to be miscible in aqueous solvents. Pure water can only dissolve hydrophilic compounds such as low molecular weight alcohols, ketones, aldehydes, amides, esters and ether. The accumulation of such compounds in water is of course limited by the partition coefficient, which will be discussed later in the article. Octanol/water partition coefficients for some compounds are also available in the literature46,47. However, the accumulation of apolar organic compounds such as alkanes in aqueous solutions will not reach concentrations that could be detected in extractables studies mimicking biopharmaceutical applications lasting up to several weeks or months. This is especially true in the case of a multilayer film materials as the layering may act to retard extractable migration48. 4.1.2

Partition Coefficient

During long extraction times it can expected that an equilibrium between the polymer phase and the liquid phase will be reached, which can be described by the Equation 1: Equation 1: / =

⁄

= ⁄

which can be rearranged for finite systems46 with = + to: Equation 2 : =

= ∗

/

Where:

/

Partition coefficient of extractables between polymer and liquid phase Concentration of extractables in the polymer phase Concentration of extractables in the liquid phase Mass of extractables in the polymer phase Mass of extractables in the liquid phase Pristine amount of extractables in the polymer (i.e. before starting the extraction experiment, whereby: = + )

Volume of polymer Volume of liquid phase

The equilibrium concentration is identical to the maximum concentration of an extractable compound that can be reached in a given system at a given temperature (here 40°C) and pressure (here ambient). The velocity for reaching the maximum or equilibrium concentration of the extractable depends on diffusion and the diffusion-influencing parameters (i.e. time, temperature and specimen geometry) in the polymer. Consequently worst-case extractables experiments should utilize solvents and solvent systems with low partition coefficient / for the extractables of interest in a given system. Extractables experiments conducted under these thermodynamic conditions should allow the user to determine “equilibrium conditions“. Therefore, we have investigated the influence of extraction temperature (23°C, 40 °C and 60°C)


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on extractables released from the film into an ethanol contact fluid. The extraction process is endothermic and can be accelerated by increasing the temperature. The influence of pressure was not investigated because our extractables studies were conducted under ambient conditions. We have gathered and calculated partition coefficients for selected chemicals in a LDPE/EtOH system in Table 3 SI. It comes out for aqueous solutions, that the Kp/l shows that most of the compounds coming from plastics will mainly remain in the plastics and only low concentration can be expected for these compounds. 4.1.3

Influence of the pH value on compound partitioning from polymers into aqueous solution

The influence of solute pH on extractables concentration was already discussed in the literature49. A suitable equation to calculate an apparent partition coefficient in dependence from the pH value for compounds which can be de-protonated (e.g. phenols organic acids) or protonated (e.g. amines) was given there. / (pH) = / / [ 1 + 10(

/

/ (pH)

!"#)

]

Partition coefficient of extractables between polymer and liquid phase Partition coefficient of extractables between polymer and liquid phase as function of the pH value

pH

pKa

pH-value of solution pKa-value of compound under consideration

Compounds that are insoluble in water can hence become soluble in an aqueous environment if they can form an ionic species by treatment with an acid or a base. The solubility of carboxylic acids (pKa = 3 to 5) and phenols (pKa = 9 to 10) in aqueous caustic solution is due to the formation of the polar (ionic) carboxylate or phenolic groups, since they are much stronger acids than water (pKa about 15). The solubility of amines in diluted aqueous acid similarly reflects the fact that they are stronger bases than water, and are converted by protonation to the polar ammonium ion. Amines are the only common class of organic compounds which are protonated in diluted aqueous acid. 4.1.4

Water modifiers

The action of chaotropic and kosmotropic agents is related to their effect on the structure and lipophilicity of water. Ammonium sulfate ((NH4)2SO4) acts as a kosmotropic salt in aqueous solutions. Guanidine salt50–55 acts as a chaotropic agent favoring the transfer of apolar groups to water and increasing the water solubility of particulate proteins and nonelectrolytes such as alcohols56. While polymers are mainly apolar, one could expect guanidine at high concentration to promote the solvation of polymer by-products.

High salt

concentrated kosmotropic solution are likely to extract hydrophilic organic substances and mixtures of different salts, often used as a neutral, isotonic buffer for cell culture could promote likewise the extraction of hydrophilic organic substances. The physico-chemical properties of water can be also changed by using a surfactant such as the polysorbate 80 which is a nonionic surfactant57. A polysorbate 80 concentration of 1% in water is above the critical


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micellar concentration of 0.012 mM 57 allowing good solvation of organic solving molecules into the aqueous medium. A 1% Polysorbate 80 solution, as water, does not make swell PE, PP and EVA. The extraction characteristic of water can be changed as well by addition of aprotic organic solvents such as dimethylsulfoxide (DMSO). Dimethyl sulfoxide (DMSO) is a polar aprotic solvent that dissolves both polar and nonpolar compounds, and it is miscible in a wide range of organic solvents including water. The dielectric constant of a solution of 10% DMSO in water typically used in biotechnological applications is close to pure water one at 298°K58: 79.0 vs 79.5, respectively 10%DMSO and pure water. It can be assumed that the influence of DMSO is negligible on the solvation of organic compounds that are rather apolar at a concentration ≤10-20%.

4.2

Polymer solvent interaction

Dissolving a polymer is different from dissolving low molecular weight compounds because of the very different dimensions of the solvent and of the polymer molecules. Dissolution of polymers is often a slow process and network polymers do not dissolve, but usually swell in the presence of solvent. Solubility is a complex function of many variables including but not limited to molecular weight44, degree of crystallinity, extent of branching and temperature. The solubility in a given solvent may vary greatly even within a given polymer class (e.g. toluene solubility of LDPE versus HDPE)59. An overview of the polymer dissolution is available in the litterature60. Several models to account for the experimentally observed dissolution mechanism of amorphous polymers have been formulated and have been reviewed extensively

61–64

. In

(bio)pharma applications alcohols like ethanol and isopropanol and their mixtures with water are preferred solvents31,65 for extractions studies. To obtain an approximation of the polymer-solvent interaction with these mixtures and other organic solvents, we used in this study Hansen’ 3D solubility parameter derivate as follow. aHildebrand and Scott introduced a concept to predict solubility in the case of low-molecular-weight ) +/,

materials and polymers, ' = ( * energy E per unit volume V

59,66,67

, where the solubility parameter ' is equal to the square root of cohesive

. One basic assumption of solubility parameter theory is that a correlation

exists between the cohesive energy density of pure substances and their mutual solubility.

Hansen

expanded this concept in an effort to account for both polar and hydrogen bonding interactions in solvent– polymer systems. The total solubility parameter (cohesive energy in MPa1/2) is separated into three separate parameters and takes into account the dispersion, polar, and hydrogen bonding effects of the solvent or solute (Equation 3)68. Equation 3: ' = ',- + ', + ',.

The combined theory of Flory–Huggins and Hildebrand–Scatchard provides a satisfactory approximation for the interpretation of most polymer–solvent data60,69. The Flory parameter, χ, can be defined in terms of Hildebrand solubility as:


10

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Equation 4: / = /0 + /. = /0 + 0

('0 !' ), 12

(s: solvent; p: polymer)

where S is the entropic term (Flory combinatorial entropy correction factor) and H is the enthalpic term of the interaction parameter. Additional interactions, polar and hydrogen bonding effects progressing from the non-polar Hildebrand solubility parameter when calculating χ, should be accounted and should be introduced from Equation 5. The Hansen HSP (Hansen Solubility Parameters), or Ra in Equation 5, model is in three-dimensional space representing the solubility of the solute and defines a “radius of interaction” for that solute60,70: ,

,

Equation 5: 1,3 = 45- − -0 7 + 58 − 80 7 + 5. − .0 7

,

where the Euclidian between the solubility parameters of polymer and solvent is the variable 9#: , and are represented D, for the dispersion, P, for the polarity/dipole–dipole, and H, for the hydrogen bonding contributions; and subscripts p and s are polymer and solvent, respectively. Combining70 both Equation 4 and Equation 5 leads to:

Equation 6: / = /0 + /. = /0 + 120 1,3 (s: solvent)

A value of 0.34 for χs was previously reported for polymer–liquid systems as an average correction and was used in this study68,71. A detailed description of the molar volume (Vs) and of the different solubility parameters is available in literature for the solvents (;< ) and the polymers (; ) to perform the calculations 44,68,72,73

.

For a polymer to be soluble in a solvent at a particular temperature, χ must be

Theoretical and practical considerations when selecting solvents for

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