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Article pubs.acs.org/OPRD
Methodology for Replacing Dipolar Aprotic Solvents Used in API Processing with Safe Hydrogen-Bond Donor and Acceptor SolventPair Mixtures Alif Duereh,† Yoshiyuki Sato,† Richard Lee Smith, Jr.,*,†,‡ and Hiroshi Inomata† †
Graduate School of Engineering, ‡Graduate School of Environmental Studies, Research Center of Supercritical Fluid Technology, Tohoku University, Aramaki Aza Aoba 6-6-11, Aoba-ku, Sendai 980-8579, Japan S Supporting Information *
ABSTRACT: A methodology is presented that allows hazardous dipolar aprotic solvents used in the pharmaceutical processing industries to be replaced with solvent-pair mixtures that consist of a hydrogen-bond donor (HBD) solvent and a hydrogen-bond acceptor (HBA) solvent. The methodology uses the solubility of the active pharmaceutical ingredient (API) in hazardous solvents to estimate the range of required solubility parameters and Kamlet−Taft parameters for the API and then intersects these ranges with the solubility parameters and Kamlet−Taft parameters of the solvent-pair mixtures to identify favorable solvent pairs and possible working compositions. Solvent pairs are ranked according to GSK safety and health scores. The methodology was applied to 13 APIs, where it was found that nonaqueous mixtures (ethanol−isopropyl acetate, ethanol−ethyl acetate, and ethanol−butyl acetate) and aqueous mixtures (water−γ-valerolactone and water−dimethyl sulfoxide) are highly ranked and applicable to many APIs. Solvent pairs were eliminated from consideration due to their inability to simultaneously satisfy Kamlet−Taft acidity, basicity, and polarity parameter constraints. The proposed methodology makes it simple to identify and rank HBD−HBA solvent-pair mixtures for replacement of dipolar aprotic solvents used in the pharmaceutical processing industries.
1. INTRODUCTION The Innovative Medicines Initiative (IMI)-CHEM21 public− private partnership lists N-methyl-2-pyrrolidone (NMP), N, Ndimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,Ndimethylacetamide (DMA), pyridine (Pyr), and hexamethyl phosphoramide (HMPA) dipolar aprotic solvents as being hazardous and suggests that those solvents should be substituted with safe solvents for processing and developing active pharmaceutical ingredients (APIs).1 Many API processing operations such as solubilization,2−4 crystallization,5,6 and reaction7 require dipolar aprotic solvents because these chemicals have low Kamlet−Taft (KT) acidity (α ≈ 0), high basicity (β > 0.6), and high polarity (π* > 0.6) that provide strong interactions with the API.2−4,7−15 Since many dipolar aprotic solvents used in processing of APIs are hazardous,1,16 their replacement with safe solvents is actively being studied through European academic chemical societies, global pharmaceutical industrial consortia, and the American Chemical Society (ACS) Green Chemistry Institute (GCI), who have produced solvent selection guides IMI-CHEM21,1 GSK2016,16 and recommendations of the ACS GCI Pharmaceutical Roundtable.5 For example, N-ethyl-2-pyrrolidone, Nbutyl-2-pyrrolidone, and 2-methyltetrahydrofuran are proposed to be alternative dipolar aprotic solvents,7,17 even though these replacement solvents still have issues in toxicity.16 One report notes that there are no acceptable substitutes for most dipolar aprotic solvents.17 Figure 1 shows a plot of various solvent groups including dipolar aprotic solvents according to their range of KT acidity, basicity, and polarity parameters.18−20 It is clear that all of the pure solvent groups shown in Figure 1 are unable to replace © 2016 American Chemical Society
dipolar aprotic solvents because the pure solvent KT parameters lack sufficiently high basicity and polarity or sufficiently low acidity. However, if lines are drawn between pairs of hydrogenbond donor (HBD) and hydrogen-bond acceptor (HBA) solvents in Figure 1, it can be seen that it may be possible for the KT parameters of the solvent-pair mixture to have favorable acidity, basicity, and polarity characteristics. The purpose of this article is to report a methodology for identifying solvent pairs that are suitable for replacing dipolar aprotic solvents used in API processing. Consider an example in the synthesis of polyimide engineering of plastics, for which hazardous dipolar aprotic solvents seem to be indispensable for solubilizing dianhydride and dianiline monomers that spontaneously react in a homogeneous solution.21,22 Insufficient KT polarity or basicity of the solvent leads to polymer precipitation and failure of the synthesis.18 In previous research, we found that several safe and renewable HBD−HBA solvent-pair mixtures could replace dipolar aprotic pure solvents used in preparing polymer precursors for engineering plastics,18 with the reason being that these mixtures form complex molecules that cause variation of the solution KT parameters and, in some cases, result in synergism.23−26 Thus, it is likely that substitution of a dipolar aprotic solvent with an HBD−HBA solvent-pair mixture in processing APIs is possible. API solubility was chosen as an example to show the possibility for solvent replacement since it is a common property required for processing and because examination of solubility data of APIs in solvents shows that many values are high in dipolar aprotic Received: November 30, 2016 Published: December 16, 2016 114
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health, environmental, and waste scores is explored for ranking solvent-pair mixtures. The objectives of this work can be summarized as follows. The first objective is to propose a methodology for identifying solvent-pair mixtures suitable for dissolution of APIs. The second objective is to show the application of the methodology by example of a target API. The third objective is to rank and analyze solvent-pair mixtures in accordance with the GSK2016 solvent selection guide and to show the potential application of the ranking to a select group of APIs. The identified solvent-pair (binary) mixtures consist of a HBD solvent and a HBA solvent that can effectively substitute a dipolar aprotic solvent according to the property of solubility. In this work, 13 APIs were studied according to available solubility data.
2. SOLUBILITY MODEL The solubility (x3) of an API (3) in a solvent-pair mixture that consists of an HBD solvent (1) and HBA solvent (2) is given by thermodynamic expressions in texts29 as ln x3 = −ln γ3 −
ΔH fus ⎛ T ⎞ ⎟ ⎜1 − RT ⎝ Tm ⎠
(1)
where ΔHfus and Tm are the enthalpy of fusion and melting point temperature of the API, respectively, and γ3 is the activity coefficient of the API in the solvent-pair mixture. Although there have been many proposed methods for calculating the activity coefficient of an API in both pure solvents and in mixed-solvent systems (e.g., Pharma Mod. UNIFAC,30 PC-SAFT,31 COSMORS32), regular solution theory was chosen to calculate the activity coefficient of the API in the solvent-pair mixtures because it requires a minimum amount of API property data (ΔHfus, Tm, VL, solubility parameter δ) and it allows simplified illustration of the methodology since solvent-pair compositions at maximum
Figure 1. Kamlet−Taft parameters for various chemical groups. Hazardous dipolar aprotic solvents include pyridine (Pyr), hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N-methyl2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). Kamlet−Taft parameters of solvents in each chemical group are given in Table S5 (Supporting Information).
max
solubility (xS2 ) can be determined without iteration (Section A in the Supporting Information). The calculated solvent-pair compositions at maximum API solubility are used to discuss one type of ranking scheme for solvent-pair mixtures.
solvents (Table S1, Supporting Information). Typical APIs have multiple HBD and HBA sites so that an HBA solvent allows strong interaction with HBD sites of the API. On the other hand, variation of the composition of an HBD−HBA solvent-pair mixture allows adjustment of the solution KT parameters to obtain comparable interactions as those for dipolar aprotic solvents.24 Although adjustment of physicochemical properties is a clear merit for solvent-pair mixtures, the determination of working composition ranges is needed for practical applications. In this work, methodology for identifying both the solvent pair and the working composition ranges that can replace pure dipolar aprotic solvents is proposed, and the solvent-pair mixtures are ranked according to GSK scores16 in safety and health. There are no comprehensive frameworks designed for ranking solvent-pair mixtures according to safety, health, environment, and waste categories. One report uses solvent composition to average safety, health, and environment (SHE) scores in the evaluation of solvent-pair mixtures for solvolysis of p-methoxybenzoyl chloride.27 However, in practical application, use of a safe solvent with a hazardous solvent as a solvent-pair mixture may not provide any safety or health benefit, even though the quantity of hazardous solvent being used is reduced, which would be highly desirable in terms of toxic chemical release.28 Thus, an averaging scheme based on identified solventpair mixture working composition ranges and operating mixture compositions for each solvent-pair mixture with GSK safety,
3. METHODOLOGY Figure 2 shows the methodology developed in this work for selecting HBD−HBA solvent-pair mixtures that can replace dipolar aprotic solvents used in processing an API. The key assumption in the methodology is that the solubility of the API in available solvents defines the range of favorable solubility parameters (δAPI window) and the range of favorable KT parameters (αAPI, βAPI, and π*API windows) of the HBD−HBA solvent-pair mixtures. The intersection of these windows defines the compositional working ranges of potential solvent-pair mixtures that are then used to identify, rank, and select suitable solvent-pair mixtures. One assumption in the methodology is the choice of high solubility of the API in the solvent-pair as a metric. Safety, health, environmental, and waste scores for the ranking of solvents are adopted from GSK solvent guides.16 Factors such as solvent reactivity with either the solute or reactants, side reactions, cocrystallization products, solvent conditions (elevated temperature or pressure), or other phenomena are out of the scope of this study but are discussed briefly in Sections 7 and 9. The methodology (Figure 2) is divided into three parts: 115
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Figure 2. Methodology for replacing dipolar aprotic solvents used in API processing with safe hydrogen-bond donor (HBD) and hydrogen-bond acceptor (HBA) solvent-pair mixtures. Steps 1−3 compile API and solvent properties (blue highlight). Steps 4−6 define required solvent-pair characteristics and identify solvent-pair mixtures and their working composition ranges (yellow highlight). Steps 7 and 8 rank and select solvent-pair mixtures (green highlight).
to determine liquid molar volume and solubility parameter (δ), whereas other properties (e.g., enthalpy of fusion and melting temperature) are taken from NIST Webbook33 and ChemSpider databases.34 In steps 2 and 3 (Figure 2), pure solvent and mixed solvent properties (Table S4) along with solubilities of the API in solvents are tabulated from literature sources (Table S5). In step 4, solubilities of the API in available solvents are used to estimate the API solubility parameter window (δAPI window) and the API KT parameter windows (αAPI, βAPI, and π*API windows). The δAPI window is defined as the favorable range of affinities (solubility parameters) required for dissolution of the API into a solvent. The αAPI, βAPI, and π*API windows are defined as the range of acidities, basicities, and polarities for which the API is known to be soluble in the solvent or solvent mixture. In step 5, the δAPI window is imposed onto the range of solubility parameters for each solvent pair to define the compositions that are possible for the given solvent pair. Then, the αAPI, βAPI, and π*API windows are imposed onto the respective solvent-pair KT parameters (α, β, and π*) versus composition plots to define the possible range of compositions that can be used to vary the acidity, basicity, or polarity of the given solvent pair. In step 6, the intersection of the range of solvent-pair solubility parameters (δpair window) with the range of solvent-pair KT parameters (αpair, βpair, and π*pair windows) gives the working range of compositions (x2,working) that satisfy all of the API solubility parameter and KT parameter criteria and allow identification of HBD−HBA solvent-pair mixtures (step 5, Figure 2).
(i) estimation of the API properties, tabulation of solvent properties, and compilation of API solubility data (steps 1−3, Figure 2); (ii) definition of solute and mixed-solvent characteristic parameter windows as criteria to determine working composition ranges and access solvent-pair mixtures (steps 4−6, Figure 2); and (iii) selection of solvent-pairs through ranking (steps 7 and 8, Figure 2). The proposed methodology is demonstrated with a database of 52 HBD−HBA solvent-pair mixtures (Tables S2 and S3, Section B in Supporting Information) for which many KT parameters and all GSK scores are available. HBD solvents used in the HBD−HBA solvent-pair mixtures (Table S2) are mainly water, methanol (MeOH), and ethanol (EtOH) because these solvents are recommended for API processing in the IMICHEM211 and GSK201616 solvent selection guides. The HBD solvent of the HBD−HBA solvent-pair mixture is determined according to its relative KT acidity value with the other solventpair member. In general, MeOH and EtOH are considered to be HBD solvents when used in nonaqueous mixtures, whereas they are considered to be HBA solvents when used as a solvent pair with water. Piecewise linear interpolation was used to calculate values from the KT parameter mixed-solvent data at any given composition. For solvent-pair mixtures in which KT parameter data were unavailable, linear (ideal) interpolation between the pure KT parameters was used. In step 1, properties of the API are estimated (Figure 2). For the APIs considered in this work (Table S4, Section B in Supporting Information), group contribution methods are used 116
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After the working range of compositions is determined, the operating composition (x2,operating) of the solvent pair is calculated for one ranking scheme, shown in the Supporting Information (Section C). In step 7 (Figure 2), solvent-pair mixtures are ranked using the geometric mean of the minimum values of the pure solvent safety and health GSK scores of the solvent-pair mixture composite score =
Smin × H min
(2)
where Smin and Hmin represent the minimum GSK safety and health scores, respectively, of the pure solvents in the solvent-pair mixture. The composite score given by eq 2 depends only on the pure solvent scores and is independent of the composition of the solvent-pair mixture. Recommended, problematic, and hazardous score ranges for solvents in Table 1 are adopted from IMICHEM211 to include a wide range of recommended solvents.
4. APPLICATION OF METHODOLOGY Paracetamol is used as an example to illustrate the methodology. Properties of paracetamol, pure and mixed-solvents (Tables S4 and S5, Section B in Supporting Information), and solubilities of paracetamol in pure and mixed solvents are tabulated (Tables S6 and S7, Section B in Supporting Information). From the available solubility data, the range of solubility parameters (δAPI window) and KT parameters (αAPI, βAPI, and π*API windows) is estimated (Figure 3a−d) according to favorable and unfavorable solvents and solvent mixtures for paracetamol dissolution. For this API, high solubility was roughly defined as 35 wt % to allow consideration of a wide range of solvents. As shown in Figure 3, the range of pure solvent and solvent-pair mixtures that shows high solubility for paracetamol defines the API solubility parameter window (16.3−30.5 MPa0.5) and the API KT parameter windows for acidity (≤0.75), basicity (≥0.62), and polarity (≥0.35). Figure 4 shows the solubility parameters and KT parameters for aqueous solvent-pair mixtures versus composition. Corresponding plots for nonaqueous HBD−HBA solvent-pair mixtures are given in the Supporting Information (Figures S1 and S2 in Section B). While the solubility parameters of solventpair mixtures have expected trends with composition (Figure 4a), the KT acidities, basicities, and polarities of solvent-pair mixtures (Figure 4b−d) are highly nonlinear due to molecular interactions.24 Transposition of the δAPI window onto the plot of solvent-pair solubility parameters (Figure 4a) provides a constraint on composition for any given solvent pair. Transposition of the αAPI, βAPI, and π*API windows onto the respective KT parameter plots (Figures 4b−d), respectively, places additional constraints on the range of compositions for the given solvent pair. Figure 5 shows plots of the solubility parameter and KT parameters versus composition for the water−acetone solventpair mixture with their respective δAPI, αAPI, βAPI, and π*API windows (Figure 5a−d, gray shaded regions). The intersection of the δAPI window with the KT αAPI, βAPI, and π*API windows (Figure 5a−d, yellow hatched regions) provides the range of working compositions for a given solvent pair and defines the range of solubility parameters (δpair window) and range of KT parameters (αpair, βpair, and π*pair windows) that are obtainable for the given solvent pair. According to the intersection of the windows (Figures 5a−d), the range of working compositions for water−acetone solvent-pair mixtures (0.42 ≤ x2 ≤ 0.80) and KT parameters (0.08 ≤ αpair ≤ 0.75; 0.62 ≤ βpair ≤ 0.68; 0.69 ≤ πpair * ≤
Figure 3. Solubility parameter window and Kamlet−Taft parameter windows (green shaded regions) according to the solubility of paracetamol in pure solvents and literature solvent pairs. Solubility data of paracetamol in solvents were obtained from the literature.2,35,43 Solubility parameter of paracetamol was estimated by group contribution.40,44 Solubility parameters45 and Kamlet−Taft parameters of pure solvents19,20 and those of the solvent-pairs were obtained from the literature.23,46 Symbols: squares, hydrogen-bond donor (HBD) solvent; circles, hydrogen-bond acceptor (HBA) solvent; triangles, hexagons, pentagons, and diamonds, HBD−HBA solvent-pair mixtures. Filled symbols indicate high solubility of solute in solvent (≥350 g of solute/kg of solvent). Unfilled symbols indicate low solubility of solute in solvent (≤350 g of solute/kg of solvent). Recommended (green symbols), problematic (orange symbols), and hazardous (red symbols) solvent rankings are according to IMI-CHEM21 and GSK solvent selection guidelines.1,16 Abbreviations: diethylamine (DEA), dimethylformamide (DMF), 1,4-dioxane (DI), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (ACN), methanol (MeOH), ethanol (EtOH), ethyl glycol (ETG), isopropanol (iPrOH), propanol (PrOH), acetone (Ace), 1-butanol (BuOH), methyl ethyl ketone (MEK), 1-pentanol (PeOH), hexanol (HxOH), heptanol (HeOH), octanol (OcOH), methyl isobutyl ketone (MIBK), ethyl acetate (EtAc).
1.09) can be known. Solvent-pair compositions that fall outside of the working composition range are unable to meet the solvent characteristic requirements given by the δAPI window and αAPI, βAPI, and π*API windows. By application of the methodology, 39 out of 52 solvent pairs could be identified as possible replacement solvents for pure dipolar aprotic solvents that dissolve paracetamol, as shown in Table 1. Table 1 shows ranking of HBD−HBA solvent-pair mixtures that were determined from composite GSK scores according to eq 2. The highest ranked solvent pairs had water or ethanol as the HBD solvent. The lowest ranked solvent pairs 117
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Figure 4. Aqueous solvent-pair mixtures of hydrogen-bond donor (HBD) and hydrogen-bond acceptor (HBA) solvent-pair mixtures showing (a) solubility parameter and Kamlet−Taft (b) acidity, (c) basicity, and (d) polarity as a function of HBA solvent (x2) mole fraction. Solubility parameter window (δAPI), acidity window (αAPI), * ) acidity are shown for basicity window (βAPI), and polarity window (πAPI paracetamol (Table 2). Abbreviations used for solvents are given in Table S5 (Supporting Information).
Figure 5. Solubility parameter and Kamlet−Taft parameters versus hydrogen-bond acceptor (HBA) solvent mole fraction for the water− acetone system. Gray shading shows applicable solubility parameter and Kamlet−Taft regions for the given solvent pair (water−acetone). Yellow hatched regions are the intersection of the solubility parameter solventpair window with the solvent-pair Kamlet−Taft parameter windows that provide the working composition range of the solvent-pair mixture. Symbols represent experimental data obtained from the literature.23
generally had a hazardous HBA solvent as one of the solvent pairs. Solvent pairs containing water or ethanol generally have favorable safety and health scores, but they are less desirable according to their environmental and waste scores (Table 1). Ethanol as the HBD solvent combined with acetate (iPrAc, EtAc, or BuAc) as the HBA solvent was favorably ranked (Table 1) as nonaqueous solvent-pair mixtures applicable to paracetamol. Water as the HBD solvent combined with DMSO, a lactone (GVL), or a ketone (Ace) was favorably ranked as aqueous solvent-pair mixtures applicable to paracetamol. The
water−acetone solvent-pair mixture (Table 1) reported in the literature35 as a favorable solvent mixture for paracetamol has a composite score evaluated in this work as problematic (4 < score < 7) due to its GSK safety score. Among the 52 solvent pairs considered, 13 solvent pairs were eliminated (Table 1) due to low basicity (H2O−ACN and H2O− GBL), high acidity (H2O−EtOH, −iPrOH, −MeOH), or inability of the solvent-pair composition to simultaneously satisfy both the basicity (β ≥ 0.62) and acidity (α ≤ 0.75) requirements (MeOH−iPrAc, −Ace, −EtAc, −BuAc, −Ans, 118
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Table 1. Ranking of Hydrogen Bond Donor−Acceptor (HBD−HBA) Solvent-Pair Mixtures for Paracetamol According to Composite Score (Equation 2) along with Working Range Compositions
a
Recommended solvent pairs (green highlight) = score 7−10, problematic solvent pairs (yellow highlight) = score 4−7, and hazardous solvent pairs (red highlight) = score 0−4 are score ranges adopted from IMI-CHEM21.1 Unfavorable solvent-pairs due to low basicity = (13) H2O−ACN and (20) H2O−GBL; high acidity = (2) H2O−EtOH, (3) H2O−iPrOH, (40) H2O−MeOH; unable to satisfy in both basicity and acidity = (25) MeOH−iPrAc, (26) MeOH−Ace, (28) MeOH−EtAc, (29) MeOH−BuAc, (30) MeOH−Ans, (34) MeOH−CPN, (38) MeOH−GBL, (43) MeOH−DI. Abbreviations of HBD−HBA solvent-pair mixtures are given in Figure 3 and Table S5 (Supporting Information).
−CPN, −GBL, −DI). None of the solvent pairs was eliminated due to polarity requirements because of the relatively wide range of acceptable values of this parameter for paracetamol. Table 1 also provides the working range of compositions for each solvent pair. Water, methanol, or ethanol combined with one of the hazardous dipolar aprotic solvents (NMP, DMF, DMSO, Pyr) generally has the widest working composition ranges. Some solvent pairs have impractically low working composition ranges of 0.04 or less (MeOH−ACN, −MTHF, −MIBK, −MEK). A wide range of working compositions of a solvent pair is highly desirable from an operational standpoint because precise solubilities of an API in solvent mixtures are generally unknown. Combination of a hazardous dipolar aprotic solvent with either water, methanol, or ethanol generally provides a wide working composition range and allows the solvent pair to replace the pure dipolar solvent, but the composite scores for all of these cases are below 6.0 (Table 1). Nevertheless, the use of such solvent pairs could possibly reduce the amount of hazardous dipolar aprotic
solvent being released into the environment, as emphasized in the U.S. EPA NIH Toxic Release Inventory.36
5. APPLICATION OF METHODOLOGY TO OTHER APIS The methodology was applied to 13 APIs (Table 2) that have available property and solubility data (Tables S6−S19, Section B in the Supporting Information). According to Tables 2 and S20− S31 (Section C, Supporting Information), many aqueous and nonaqueous HBD−HBA solvent-pair mixtures can replace dipolar aprotic solvents. Solvent-pair mixtures discussed below are highlighted based on the ranking of their composite GSK scores according to eq 2. Among the nonaqueous solvent pairs, EtOH−iPrAc, EtOH− EtAc, and EtOH−BuAc are highly ranked and can be broadly applied to most of the APIs in Table 2, except sulfadiazine, due to the high basicity and high polarity required for that API. Among the aqueous solvent pairs, water−EtOH, water−iPrOH, water− GVL, and water−DMSO are highly ranked and can be broadly applied to all 13 APIs (Table 2). The top-ranked HBD−HBA 119
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Table 2. Molecular Weight (Mw), Hydrogen-Bond Donor (HBD) and Hydrogen-Bond Acceptor (HBA) Site Numbers (Site No.), and Solubility Parameter (δ) of APIs at 25 °C along with Solubility Parameter (δAPI), Kamlet−Taft Acidity (αAPI), Basicity (βAPI), and Polarity (π*API) Windows for Dissolution Determined from Available Solubility Data of APIs in Pure and Mixed Solvents
a Estimated by the Stefanis and Panayiotou group contribution method.40,44 bAcidity window (αAPI) obtained at 50 wt % of the solubilities of APIs between dimethylformamide and methanol. cBasicity (αAPI) and polarity (αAPI) windows obtained at 50 wt % of the solubilities of sulfadiazine between dimethylformamide and acetone. dDetermined from a database of 52 primarily renewable HBD−HBA solvent-pair mixtures, with hazardous HBA solvent pairs being including for reference.
6. ALTERNATE RANKING SCHEME
solvent-pair mixtures (Table 2) for each API are similar, since the calculation for ranking solvent-pair mixtures is based on minimum values of the pure solvent safety and health GSK scores (eq 2) that do not depend on working composition ranges of the solvent-pair mixtures. The ranking of HBD−HBA solventpair mixtures calculated from their working composition ranges is discussed in the next section.
A ranking scheme that uses weights with the GSK scores to account for composition of the solvent-pair mixture within a given GSK category with the purpose of minimizing the amount of HBA solvent used can be explored. Safety, health, environmental impact, and waste scores obtained from the GSK2016 solvent guide16 were used to weight according to properties of the solvent-pair mixture and make averages according to the 120
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The number of applicable HBD−HBA solvent pairs for piroxicam, sulfamethoxypyridazine, and sulfadiazine (Table 2) is much lower than those for the other APIs because these APIs have a large number of HBD and HBA sites that promote strong solute−solute interactions. Thus, the dissolution of these APIs requires solvent pairs to have both strong hydrogen-bonding donor and acceptor functional groups to overcome the solute− solute self-interactions. Other APIs that have many HBD and HBA site numbers and strong hydrogen-bonding donor and acceptor functional groups can be expected to have fewer applicable solvent-pair mixtures among those considered in Table S2 (Supporting Information). Nevertheless, the proposed methodology can be expected to identify possible replacement solvent-pair mixtures for API processing steps that require dipolar aprotic solvents. Possible side reactions due to the reactivity of the substituted solvent with the solute must be considered in any solvent replacement when reactions (e.g., nucleophilic substitution) are involved. For example, Schiff base formation and hydrolysis38 for the nucleophilic substitution reaction for paracetamol synthesis can possibly occur, since p-aminophenol reactants contain amine functional groups that can undergo unwanted reactions with solvent mixed-pair mixtures containing carbonyl groups (e.g., ketones, lactones, and aldehydes). API solubility in solvents that is too high can also cause difficulties in solvent removal and purification due to strong solute−solvent interaction or high boiling point temperature solvents. Thus, residual solvent content in APIs must be considered according to the ICH limit3,39 and the solvent-pair mixture properties.
recommended GSK method to obtain a composite score (detailed calculations are given in Section C, Supporting Information). Tables S32−S41 (Section C, Supporting Information) show rankings of HBD−HBA solvent-pair mixtures for all APIs based on solvent composition, on a mass basis. Among the nonaqueous solvent pairs ranked, EtOH−GVL and EtOH−GBL can be broadly applied to most of the APIs, as summarized in Table S45, except for those with a sulfonyl group. EtOH−CPN is one of the top-ranked solvent pairs for APIs that contain a carboxylic acid group (Table S45). The EtOH−iPrAc and EtOH−CPN solvent pairs are ranked high for two APIs (piroxicam and sulfamethoxy pyridazine) with a sulfonyl group, but they are not applicable to sulfadiazine due to the high basicity and high polarity required for that API. Among the aqueous solvent pairs ranked according to solvent composition on a mass basis, water−EtOH, water−iPrOH, and water−DMSO are highly ranked and can be broadly applied to all 13 APIs (Table S45). Water−GBL and water−EtOH solvent pairs are highly ranked for APIs that contain a carboxylic acid group (Table S45). Water−tBuOH is one of the solvent pairs that is top-ranked for APIs that contain a sulfonyl group (Table S45). The number of applicable HBD−HBA solvent-pair mixtures determined in both ranking schemes (minimum value and weight-averaged composition) for all APIs is similar, since the applicable HBD−HBA solvent-pair mixtures are identified from physicochemical properties of solvents using solubility and KT parameters. However, the top-ranked HBD−HBA solvent-pair mixtures determined by both ranking schemes for all APIs (Table 2 and Table S45) are different, except for APIs that contain a sulfonyl group, since the number of applicable solvent-pair mixtures is greatly limited. A framework for ranking solvent-pair mixtures is challenging and should be a future research topic. The methodology proposed in this work for identifying HBD−HBA solvent-pair mixtures and the working composition ranges is independent of the ranking scheme and the thermodynamic model used for calculating API solubility.
8. REFINEMENTS TO THE METHODOLOGY AND EXTENSIONS Many authors have proposed the use of solvent mixtures to replace solvents or solvent mixtures. However, this work considers the combination of an HBD solvent with an HBA solvent along with its mixture solubility parameters and mixture KT parameters and the respective solubility parameter and KT parameter windows of the API in the present solvents to quantify a working composition region for a given solvent pair, which is an original point of this research. In the methodology for one possible ranking scheme (Section C, Supporting Information), regular solution theory is used; however, more sophisticated theories, such as Pharma Mod. UNIFAC,30 PC-SAFT,31 COSMO-RS,32 would allow one to have a more certain assessment of the solubility of the API in the solvent-pair mixture so that the framework would be rigorous. The methodology might be adapted for use with Hansen partial solubility parameters for an API, as determined by Panayiatou.40 However, this would require a framework for determining the partial solubility parameters for solvent−solvent interactions. Safety, health, environmental, and waste scores for ranking solvent-pair mixtures can be adapted for other solvent selection guidelines such as IMI-CHEM21,1 Sanofi,39 and AstraZeneca,41 depending on user objectives. In the evaluation of the KT parameter windows for the API, indicator-centric values, which are based on local composition effects for specific dyes, were used due to the limited amount of mixture property data available. To advance the methodology, it would be preferable to determine API-centric KT parameters, which are based on local composition effects for the solute from spectral measurements, for determination of the API-centric KT parameter windows and to include the effect of temperature.26
7. DISCUSSION OF SOLVENT PAIRS A combination of water, methanol, or ethanol with a hazardous dipolar aprotic solvent (e.g., DMSO) generally provides a wide range of working compositions as previously mentioned and allows the solvent pair to replace many pure dipolar aprotic solvents. Although pure DMSO has waste and recyclability issues16 due to its relative high melting and boiling temperatures, water−DMSO, methanol−DMSO, or ethanol−DMSO solventpair mixtures might be widely applicable to API processing, since they have high polarity (π* > 1) and have a wide range of acidities (0 < α < 1) and basicities (0.47 < β < 0.78) and the eutectic temperature of these solvent-pair mixtures is lower than that of pure DMSO (20 °C).37 Renewable or bioresource-derived solvents are important when considering sustainability. As HBA solvents, both GVL and GBL can be combined with water to have high polarities and a wide range of acidities, and their solvent-pair basicity tends to have synergistic behavior due to complex HBD−HBA molecules formed.24 The water−GVL and EtOH−GVL solvent-pair mixtures are highly ranked when solvent-pair composition is used with other ranking schemes as discussed in the previous section. 121
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methodology, which uses the API solubility parameter window and API-KT parameter windows, relies on determining a working composition range for each solvent pair that allows it to be ranked or eliminated. The methodology presented is simple, efficient, and effective for identifying and ranking HBD− HBA solvent-pair mixtures to replace dipolar aprotic solvents, and it has application to other API processes such as crystallization or chromatography and other non-API processes related to biomass or polymers.
Such an undertaking would allow local composition influence to be elucidated for target pharmaceuticals. The application of the preferential solvation model to API-centric KT mixed-solvent values could allow better theoretical understanding of the interactions of an API with the solvent-pair mixtures.26 The proposed methodology is applicable to identify HBD− HBA solvent-pair mixtures at a fixed temperature, since API solubility data, solubility parameter, and KT parameters of the solvent were obtained at a constant temperature of 25 °C. Thus, the effect of temperature should be considered because temperature has a large effect on API dissolution and solvent properties.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00401. Tables S1−S5 and S6−19 contain properties and API solubilities. Tables S20−S31 provide ranking of HBD− HBA solvent-pair mixtures for other APIs (beside Table 1) based on eq 2. Table S32−S44 provide ranking of HBD− HBA solvent-pair mixtures for all APIs based on HBA solvent composition (mass basis). Table S45 shows comparison of ranking schemes (minimum value and weight-averaged composition) of solvent-pair mixtures. Figures S1 and S2 show solubility parameters and Kamlet−Taft parameters versus composition for ethanol−HBA and methanol−HBA solvent-pair mixtures (PDF) Excel file that allows readers to perform their own calculations and explore concepts presented in this article, supplied strictly for educational and instructional purposes only (XLSX)
9. OTHER APPLICATIONS Several other applications can be addressed in the context of the present methodology. First, the focus of the present study is on high API solubility. Equally important could be methodology to focus on low API solubility that is required for inducing crystallization. Paracetamol is considered to illustrate the methodology for crystallization using Figure 5, which shows the water−acetone solvent-pair mixture. Assuming that the API (paracetamol) is dissolved in the solvent-pair mixture within the working composition (Figure 5), either adding sufficient acetone or sufficient water such that the composition is outside of the working composition range will cause precipitation. Namely, adding acetone will cause a decrease in the solubility parameter, acidity, basicity, and polarity (Figure 5), all of which are favorable for inducing precipitation of the API. The addition of water to the API dissolved in a solvent-pair mixture in the working composition range (Figure 5) will induce precipitation of the API due to high acidity but not due to basicity and polarity. The nature of these effects combined with changes in temperature on kinetics, crystal habit, solid morphology, crystal growth, cocrystal formation, and other phenomena can provide the means to form the desired products in a single solvent-pair mixture. Another application of the methodology would be for choosing solvent-pair mixtures that exclude certain impurities due to selectivity. For this case, the working composition range would be further narrowed to minimize the solubility of the impurity within the initially identified working composition range. The methodology is applicable to choosing solvents for processing non-API chemicals such as lignin. Dissolution and fractionation of lignin that uses solvent-pair mixtures has reported8,15 that HBD−HBA solvent-pair mixtures (e.g., H2O−GVL mixture) show higher lignin solubility than that of HBA−HBA solvent-pair mixtures (e.g., DMSO−GVL and DMF−GVL mixtures). The proposed methodology can be applied to identify HBD−HBA solvent-pair mixtures and their working composition ranges for lignin dissolution and fractionation. The present methodology is considered to be applicable to chromatographic separations or purification procedures. Solvent mixtures with methanol can possibly replace dichloromethane used in chromatographic purification procedures.42
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel (Fax): +81-22-7957282. ORCID
Alif Duereh: 0000-0003-0170-8601 Richard Lee Smith Jr.: 0000-0002-9174-7681 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors wish to gratefully acknowledge the Research Center of Supercritical Fluids for support of this research. ABBREVIATIONS AND SYMBOLS
Abbreviations
Ace ACN Ans API BuAc CPN DI DMSO EtAc EtOH GBL GVL HBA HBD
10. CONCLUSIONS In this work, a methodology was proposed for replacing dipolar aprotic solvents used in the API industry with HBD−HBA solvent-pair mixtures. For the 13 APIs and 52 solvent-pair mixtures considered, the methodology could be used to identify and rank solvent pairs that had favorable GSK scores. The 122
acetone acetonitrile anisole active pharmaceutical ingredients (component 3) butyl acetate cyclopentanone 1,4-dioxane dimethyl sulfoxide ethyl acetate ethanol γ-butyrolactone γ-valerolactone hydrogen-bond acceptor solvent (component 2) hydrogen-bond donor solvent (component 1) DOI: 10.1021/acs.oprd.6b00401 Org. Process Res. Dev. 2017, 21, 114−124
Organic Process Research & Development IMI iPrAc iPrOH KT MeOH tBuOH
Article
(8) Xue, Z.; Zhao, X.; Sun, R.-c.; Mu, T. Biomass-Derived γValerolactone-Based Solvent Systems for Highly Efficient Dissolution of Various Lignins: Dissolution Behavior and Mechanism Study. ACS Sustainable Chem. Eng. 2016, 4, 3864−3870. (9) Mu, L.; Shi, Y.; Chen, L.; Ji, T.; Yuan, R.; Wang, H.; Zhu, J. [NMethyl-2-pyrrolidone][C1-C4 carboxylic acid]: A Novel Solvent System with Exceptional Lignin Solubility. Chem. Commun. 2015, 51, 13554−13557. (10) Shuai, L.; Luterbacher, J. Organic Solvent Effects in Biomass Conversion Reactions. ChemSusChem 2016, 9, 133−155. (11) Monbaliu, J.-C. M.; Stelzer, T.; Revalor, E.; Weeranoppanant, N.; Jensen, K. F.; Myerson, A. S. Compact and Integrated Approach for Advanced End-to-End Production, Purification, and Aqueous Formulation of Lidocaine Hydrochloride. Org. Process Res. Dev. 2016, 20, 1347−1353. (12) Caes, B. R.; Teixeira, R. E.; Knapp, K. G.; Raines, R. T. Biomass to Furanics: Renewable Routes to Chemicals and Fuels. ACS Sustainable Chem. Eng. 2015, 3, 2591−2605. (13) Huang, Y.-B.; Xin, P.-P.; Li, J.-X.; Shao, Y.-Y.; Huang, C.-B.; Pan, H. Room-Temperature Dissolution and Mechanistic Investigation of Cellulose in a Tetra-Butylammonium Acetate/Dimethyl Sulfoxide System. ACS Sustainable Chem. Eng. 2016, 4, 2286−2294. (14) Zhang, C.; Liu, R.; Xiang, J.; Kang, H.; Liu, Z.; Huang, Y. Dissolution Mechanism of Cellulose in N,N-Dimethylacetamide/ Lithium Chloride: Revisiting through Molecular Interactions. J. Phys. Chem. B 2014, 118, 9507−9514. (15) Fang, W.; Sixta, H. Advanced Biorefinery Based on the Fractionation of Biomass in γ-Valerolactone and Water. ChemSusChem 2015, 8, 73−76. (16) Alder, C. M.; Hayler, J. D.; Henderson, R. K.; Redman, A. M.; Shukla, L.; Shuster, L. E.; Sneddon, H. F. Updating and Further Expanding GSK’s Solvent Sustainability Guide. Green Chem. 2016, 18, 3879−3890. (17) Diorazio, L. J.; Hose, D. R. J.; Adlington, N. K. Toward a More Holistic Framework for Solvent Selection. Org. Process Res. Dev. 2016, 20, 760−773. (18) Duereh, A.; Sato, Y.; Smith, R. L.; Inomata, H. Replacement of Hazardous Chemicals Used in Engineering Plastics with Safe and Renewable Hydrogen-Bond Donor and Acceptor Solvent-Pair Mixtures. ACS Sustainable Chem. Eng. 2015, 3, 1881−1889. (19) Marcus, Y. Solvent Mixtures: Properties and Selective Solvation; Marcel Dekker: New York, 2002. (20) Marcus, Y. The Properties of Organic Liquids That Are Relevant to Their Use as Solvating Solvents. Chem. Soc. Rev. 1993, 22, 409−416. (21) Sroog, C. E. Polyimides. Prog. Polym. Sci. 1991, 16, 561−694. (22) Ghosh, A.; Sen, S. K.; Banerjee, S.; Voit, B. Solubility Improvements in Aromatic Polyimides by Macromolecular Engineering. RSC Adv. 2012, 2, 5900−5926. (23) Marcus, Y. The Use of Chemical Probes for the Characterization of Solvent Mixtures. Part 2. Aqueous mixtures. J. Chem. Soc., Perkin Trans. 2 1994, 8, 1751−1758. (24) Duereh, A.; Sato, Y.; Smith, R. L.; Inomata, H. Analysis of the Cybotactic Region of Two Renewable Lactone−Water Mixed-Solvent Systems that Exhibit Synergistic Kamlet−Taft Basicity. J. Phys. Chem. B 2016, 120, 4467−4481. (25) García, B.; Aparicio, S.; Alcalde, R.; Ruiz, R.; Dávila, M. J.; Leal, J. M. Characterization of Lactam-Containing Binary Solvents by Solvatochromic Indicators. J. Phys. Chem. B 2004, 108, 3024−3029. (26) Duereh, A.; Sato, Y.; Smith, R. L.; Inomata, H. Spectroscopic Analysis of Binary Mixed-Solvent-Polyimide Precursor Systems with the Preferential Solvation Model for Determining Solute-Centric Kamlet− Taft Solvatochromic Parameters. J. Phys. Chem. B 2015, 119, 14738− 14749. (27) Capello, C.; Fischer, U.; Hungerbühler, K. What is a Green Solvent? A Comprehensive Framework for the Environmental Assessment of Solvents. Green Chem. 2007, 9, 927−934. (28) Lim, S.-R.; Lam, C. W.; Schoenung, J. M. Quantity-Based and Toxicity-Based Evaluation of the U.S. Toxics Release Inventory. J. Hazard. Mater. 2010, 178, 49−56.
Innovative Medicines Initiative-CHEM21 isopropyl acetate isopropanol Kamlet−Taft parameters methanol tert-butanol
Latin Symbols
E e H ΔHfus Mw R S Sw Tm VL W w x
environment score from GSK solvent selection according to eq (S9) weights calculated from ΔHfus (eq S11) health score from GSK solvent selection according to eq S8 enthalpy of fusion molecular weight universal gas constant safety score from GSK solvent selection according to eq S7 the mass of solvent required per mass of API at the operating composition melting point temperature liquid molar volume waste score from GSK solvent selection according to eq S10 weights calculated from Sw (eq S12) mole fraction of solvent i
Greek Symbols
α β δ γ π*
acidity Kamlet−Taft solvatochromic parameter basicity Kamlet−Taft solvatochromic parameter solubility parameter activity coefficient polarity Kamlet−Taft solvatochromic parameter
Superscript
Smax maximum solubility Subscripts
1 2 3 min operating pair
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HBD solvent HBA solvent API solute minimum GSK score of solvent-pair mixture range of useable mole fractions binary HBD−HBA solvent-pair mixture
REFERENCES
(1) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; AbouShehada, S.; Dunn, P. J. CHEM21 Selection Guide of Classical- and Less Classical-Solvents. Green Chem. 2016, 18, 288−296. (2) Jouyban, A. Handbook of Solubility Data for Pharmaceuticals; CRC Press: Boca Raton, FL, 2009. (3) Cue, B. W.; Zhang, J. Green Process Chemistry in the Pharmaceutical Industry. Green Chem. Lett. Rev. 2009, 2, 193−211. (4) Jouyban, A.; Panahi-Azar, V.; Khonsari, F. Solubility of Salicylic Acid in Ethanol, Propylene Glycol, and N-Methyl-2-Pyrrolidone at Various Temperatures and Their Binary Mixtures at 298.2 K. J. Mol. Liq. 2011, 160, 14−16. (5) Hellstén, S.; Qu, H.; Louhi-Kultanen, M. Screening of Binary Solvent Mixtures and Solvate Formation of Indomethacin. Chem. Eng. Technol. 2011, 34, 1667−1674. (6) Jiménez-González.; et al. Key Green Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers. Org. Process Res. Dev. 2011, 15, 900− 911. (7) Ashcroft, C. P.; Dunn, P. J.; Hayler, J. D.; Wells, A. S. Survey of Solvent Usage in Papers Published in Org. Process Res. Dev.1997− 2012. Org. Process Res. Dev. 2015, 19, 740−747. 123
DOI: 10.1021/acs.oprd.6b00401 Org. Process Res. Dev. 2017, 21, 114−124
Organic Process Research & Development
Article
(29) Sandler, S. I. Chemical, Biochemical, and Engineering Thermodynamics, 4th ed.; John Wiley: Hoboken, NJ, 2006. (30) Diedrichs, A.; Gmehling, J. Solubility Calculation of Active Pharmaceutical Ingredients in Alkanes, Alcohols, Water and their Mixtures Using Various Activity Coefficient Models. Ind. Eng. Chem. Res. 2011, 50, 1757−1769. (31) Ruether, F.; Sadowski, G. Modeling the Solubility of Pharmaceuticals in Pure Solvents and Solvent Mixtures for Drug Process Design. J. Pharm. Sci. 2009, 98, 4205−4215. (32) Harini, M.; Adhikari, J.; Rani, K. Y. A Review on Property Estimation Methods and Computational Schemes for Rational Solvent Design: A Focus on Pharmaceuticals. Ind. Eng. Chem. Res. 2013, 52, 6869−6893. (33) NIST Chemistry WebBook. http://webbook.nist.gov/chemistry/ (accessed October 2016). (34) Chemical Identifier Search. http://www.chemspider.com/ (accessed October 2016). (35) Granberg, R. A.; Rasmuson, Å. C. Solubility of Paracetamol in Binary and Ternary Mixtures of Water + Acetone + Toluene. J. Chem. Eng. Data 2000, 45, 478−483. (36) Toxic Release Inventory database (TOXMAP). https://toxmap. nlm.nih.gov/toxmap/ (accessed November 2016). (37) Kirchner, B.; Reiher, M. The Secret of Dimethyl Sulfoxide−Water Mixtures. A Quantum Chemical Study of 1DMSO−nWater Clusters. J. Am. Chem. Soc. 2002, 124, 6206−6215. (38) Cordes, E. H.; Jencks, W. P. On the Mechanism of Schiff Base Formation and Hydrolysis. J. Am. Chem. Soc. 1962, 84, 832−837. (39) Prat, D.; Pardigon, O.; Flemming, H.-W.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum, E.; Senac, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Sanofi’s Solvent Selection Guide: A Step Toward More Sustainable Processes. Org. Process Res. Dev. 2013, 17, 1517−1525. (40) Stefanis, E.; Panayiotou, C. A New Expanded Solubility Parameter Approach. Int. J. Pharm. 2012, 426, 29−43. (41) Hargreaves, C. R.; Manley, J. B. ACS GCI Pharmaceutical Roundtable: Collaboration To Deliver a Solvent Selection Guide for the Pharmaceutical Industry, 2008. https://www.acs.org/content/dam/ acsorg/greenchemistry/industriainnovation/roundtable/solventselection-guide.pdf (accessed November 2016). (42) Taygerly, J. P.; Miller, L. M.; Yee, A.; Peterson, E. A. A Convenient Guide to Help Select Replacement Solvents for Dichloromethane in Chromatography. Green Chem. 2012, 14, 3020−3025. (43) Granberg, R. A.; Rasmuson, Å. C. Solubility of Paracetamol in Pure Solvents. J. Chem. Eng. Data 1999, 44, 1391−1395. (44) Stefanis, E.; Panayiotou, C. Prediction of Hansen Solubility Parameters with a New Group-Contribution Method. Int. J. Thermophys. 2008, 29, 568−585. (45) Hansen, C. M. Hansen Solubility Parameters: A User’s Handbook; CRC Press: Boca Raton, FL, 2007. (46) Casassas, E.; Fonrodona, G.; de Juan, A. J. Solvatochromic Parameters for Binary Mixtures and a Correlation with Equilibrium Constants. Part I. Dioxane-Water Mixtures. J. Solution Chem. 1992, 21, 147−162.
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DOI: 10.1021/acs.oprd.6b00401 Org. Process Res. Dev. 2017, 21, 114−124
