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SOLUBILITY OF GLP-1 PEPTIDE

20210261642 · 2021-08-26

    Inventors

    Cpc classification

    International classification

    Abstract

    The present inventions relates to methods involving incubation of undissolved and/or insoluble GLP-1 peptide in solutions or suspensions comprising one or more organic solvents.

    Claims

    1. A method for dissolving undissolved and/or insoluble GLP-1 peptides into active, soluble GLP-1 peptides in solutions or suspensions comprising water and one or more organic solvents; comprising the steps of: (a) obtaining a first composition comprising undissolved and/or insoluble GLP-1 peptide and the organic solvent acetonitrile or DMF, wherein said first composition is in the form of a solution or a suspension; and (b) incubating said first composition at a temperature in the range of 2-85° C., and when said organic solvent is DMF then said incubating is carried out for a period of at least 20 minutes and (i) at a pH of less than 5.0 and at a concentration of said DMF in the range of 5-28%(w/w), or (ii) at a pH in the range of 5.0-5.5 and at a concentration of said DMF in the range of 0-35%(w/w); or when said organic solvent is acetonitrile then said incubating is carried out for a period of at least 2 minutes and (i) at a pH of less than 6.0 and at a concentration of said acetonitrile of at least 30%(w/w), (ii) at a pH of less than 3.5 and at a concentration of said acetonitrile of at least 14%(w/w), or (iii) if said temperature is at least 50° C. then (1) at a pH in the range of 5.5-6.0 and at a concentration of said acetonitrile of less than 10%(w/w), or (2) at a pH of less than 3.5; and wherein the undissolved and/or insoluble GLP-1 peptide is liraglutide.

    2. The method according to claim 1, wherein said method provides an increase in dissolved liraglutide by at least 0.5 mg/ml after an incubation period of 3 hours, optionally determined as described in Assay (I) herein.

    3. The method according to claim 1, wherein the temperature of said incubation in step (b) is selected from the group consisting of 2-40° C., 40-85° C. or 10-50° C.

    4. The method according to claim 1, wherein said first composition is in the form of a solution or a suspension.

    5. The method according to claim 1, wherein said organic solvent is DMF, and in step (b)(i) the concentration of said DMF is in the range of 7-23%(w/w).

    6. The method according to claim 5, wherein said period is at least 1 hour.

    7. The method according to claim 1 wherein said organic solvent is DMF, and in step (b)(i) a. said pH is less than 3.8, b. the concentration of said DMF is in the range of 9-25%(w/w), and c. said period is at least 8 hours.

    8. The method according to claim 1 wherein said organic solvent is DMF, and in step (b) if the incubation time is at least 8 hours, then the incubation is carried out (i) at a pH of less than 5.0 and at a concentration of said DMF in the range of 2-40%(w/w); or (ii) at a pH in the range of 5.0-6.0 and at a concentration of said DMF in the range of 0-40%(w/w).

    9. The method according to claim 1, wherein said organic solvent is DMF, and in step (b)(ii) the concentration of said DMF is up to 20%(w/w) or up to 19%(w/w).

    10. The method according to claim 1, wherein said organic solvent is acetonitrile, and in step (b)(ii) the concentration of said acetonitrile is at least 20%(w/w) or at least 55%(w/w).

    11. The method according to claim 1, wherein said organic solvent is acetonitrile, and in step (b)(ii) said pH is less than 3.4 or less than 3.2.

    12. The method according to claim 1, wherein said organic solvent is acetonitrile, and in step (b)(ii) said period is up to 16 hours or in the range of 5 min to 20 hours.

    13. The method according to claim 1, wherein said organic solvent is acetonitrile, and in step (b)(iii)(2) the concentration of said acetonitrile is at least 40%(w/w) or at least 45%(w/w).

    14. The method according to claim 1, wherein said organic solvent is acetonitrile, and in step (b)(ii) or in step (b)(iii)(2) said pH is less than 3.4 or less than 3.3.

    15. The method according to claim 1, wherein said method comprises a step of obtaining a composition comprising substantially no acetonitrile or DMF.

    Description

    EXAMPLES

    List of Abbreviations

    [0258] CAPS: N-cyclohexyl-3-am inopropanesulfonic acid

    [0259] DMSO: Dimethyl sulfoxide

    [0260] EtOH: Ethanol

    [0261] HEPES: 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid

    [0262] MeCN: Acetonitrile

    [0263] MES: 2-(N-morpholino)ethanesulfonic acid

    [0264] ISOP: Isopropanol

    General Methods

    [0265] Assay (I): Determination of Solubility

    96-Well Plate Preparation

    [0266] 96-well plates containing target peptide in a solid form were prepared in one of two ways:

    [0267] Method 1 (evaporation): Addition of 100 μl stock solution of said peptide at a concentration of 4-6 mg/ml to each well of a 96-well half area plate (150 μl well size). Subsequently the solvent was evaporated by applying a vacuum until the solvent was completely removed.

    [0268] Method 2 (precipitation): Addition of a certain volume of a stock solution of said peptide containing to each well of a 96-well half area plate followed by the addition of a certain volume of concentrated phosphoric acid to obtain a pH of 4.6 followed by addition of a certain volume of ethanol resulting in a final ethanol concentration of 20% v/v. Subsequently the plate was stored at 4° C. for 1 h and then centrifuged at 4,000 rpm for 20 min. Finally the supernatant was removed. The concentration of the stock solution was chosen in a way that the final amount of peptide after supernatant removal was >0.4 mg per well.

    [0269] In both cases the stock solution was prepared by adding de-ionized water to a certain amount of powder of said peptide followed by a stepwise addition of small amounts of a concentrated sodium hydroxide solution until said peptide was completely in solution.

    Solubility Measurement

    [0270] To determine solubility of a target peptide at different pH and organic solvent concentrations, two different buffer systems were used in independent experiments to cover the whole range from pH 3.0 to pH 11.0. Buffer system 1 covers pH 3.0-7.5 and buffer system 2 covers pH 7.5-11.0. For each buffer system 96 different solvent compositions were premixed in the following way: [0271] 1. A low pH buffer (adjusted to either pH 3.0 or pH 7.5) and a high pH buffer (adjusted to either pH 7.5 or pH 11.0) were mixed at 8 different ratios to obtain values between pH 3.0 and pH 7.5 or pH 7.5 and pH 11.0, respectively. The total volume after mixing was 300 μl. [0272] 2. 12 different amounts of organic solvent were then added to these buffers to obtain organic solvent (e.g. ethanol) concentrations between 0 and 70% w/w. [0273] 3. Water was then added to obtain a total weight of 1.0 g of solvent in each well.

    [0274] After preparing the 96 different solvent systems, 100 μl of each system was transferred to the 96-well plate containing the solid form of the target peptide (prepared as described in the section “96-well plate preparation”). The plate was then stored at a given temperature (between 5° C. and 70° C.) for a given time on a rotating shaker set to 400 rpm. At regular time intervals the plate was centrifuged (4,000 rpm for 10 min) and a 10 μl sample was taken from each well. The samples were then analysed by UV absorption at 280 nm for peptide quantification. Peptide concentration results are given as UV absorption at 280 nm of the sample subtracted UV absorption at 280 nm of a well comprising 10 μl water.

    [0275] The buffers used were as follows: [0276] Buffer system 1 (for the pH range from pH 3.0-7.5)

    TABLE-US-00004 Component Concentration [mM] Formic acid 91 Acetic acid 60 MES 88 HEPES 94 [0277] Buffer system 2 (for the pH ranae from pH 7.5-11.0)

    TABLE-US-00005 Component Concentration [mM] HEPES 121 Histidine 85 CAPS 128

    Assay (II): In Vitro Potency of GLP-1 Peptides (CRE Luciferase; Whole Cells)

    [0278] The purpose of this example is to test the activity, also referred to as potency, of GLP-1 peptides in vitro. The in vitro potency is the measure of human GLP-1 receptor activation in a whole cell assay.

    [0279] Principle: In vitro potency is determined by measuring the response of the human GLP-1 receptor in a reporter gene assay. The assay is performed in a stably transfected BHK cell line that expresses the human GLP-1 receptor and contains the DNA for the cAMP response element (CRE) coupled to a promoter and the gene for firefly luciferase (CRE luciferase). When the human GLP-1 receptor is activated it results in the production of cAMP, which in turn results in the luciferase protein being expressed. When assay incubation is completed the luciferase substrate (luciferin) is added and the enzyme converts luciferin to oxyluciferin to produce bioluminescence. The luminescence is measured as the readout for the assay.

    [0280] Cell culture and preparation: The cells used in this assay (e.g. clone FCW467-12A/KZ10-1) are BHK cells with BHKTS13 as a parent cell line. The cells are derived from a clone (e.g. FCW467-12A) that expresses the human GLP-1 receptor and are established by further transfection with CRE luciferase to obtain the current clone. The cells are cultured at 5% CO.sub.2 in Cell Culture Medium. They are aliquoted and stored in liquid nitrogen. Before each assay an aliquot is taken up and washed twice in PBS before being suspended at the desired concentration in the assay specific buffer. For 96-well plates the suspension is made to give a final concentration of 5×10.sup.3 cells/well.

    [0281] Materials: The following chemicals may be used in the assay: Pluronic F-68 (10%) (Gibco 2404), ovalbumin (Sigma A5503), DMEM w/o phenol red (Gibco 11880-028), 1 M Hepes (Gibco 15630), Glutamax 100× (Gibco 35050) and steadylite plus (PerkinElmer 6016757).

    [0282] Buffers: Cell Culture Medium consists of DMEM medium with 10% FBS (Fetal Bovine Serum; Invitrogen 16140-071), 1 mg/ml G418 (Invitrogen 15140-122), 240 nM MTX (methotrexate; Sigma M9929) and 1% pen/strep (penicillin/streptomycin; Invitrogen 15140-122). Assay Medium consists of DMEM w/o phenol red, 10 mM Hepes and lx Glutamax. Assay Buffer consists of 2% ovalbumin and 0.2% Pluronic F-68 in Assay Medium.

    [0283] Procedure: 1) Cell stocks are thawed in a 37° C. water bath. 2) Cells are washed three times in PBS. 3) The cells are counted and adjusted to 5×10.sup.3 cells/50 μl (1×10.sup.5 cells/ml) in Assay Medium; a 50 μlaliquot of cells is transferred to each well in the assay plate. 4) Stocks of the test compounds (and reference compounds, if any) are diluted to a concentration of 0.2 μM in Assay Buffer; compounds are diluted 10-fold to give the following concentrations: 2×10.sup.−7 M, 2×10.sup.−5 M; 2×10.sup.−9 M, 2×10.sup.−10 M, 2×10.sup.−11 M, 2×10.sup.−12 M, 2×10.sup.−13 M, and 2×10.sup.−14 M. 5) A 50 μl aliquot of compound or blank is transferred from the dilution plate to the assay plate; compounds are tested at the following final concentrations: 1×10.sup.−7 M, 1×10.sup.−5 M; 1×10.sup.−9 M, 1×10.sup.−10 M, 1×10.sup.−11 M, 1×10.sup.−12 M, 1×10.sup.−13 M, and 1×10.sup.−14 M. 6) The assay plate is incubated for 3 h in a 5% CO.sub.2 incubator at 37° C. 7) The assay plate is removed from the incubator and allowed to stand at room temperature for 15 min. 8) A 100 μl aliquot of steadylite plus reagent is added to each well of the assay plate (reagent was light sensitive). 9) Each assay plate is covered with aluminium foil to protect it from light and shaken for 30 min at room temperature. 10) Each assay plate is read in a plate reading instrument, e.g. Packard TopCount NXT.

    [0284] Calculations and Results: The data from the plate reading instrument are transferred to software (e.g. GraphPad Prism) which performs a non-linear regression (log(agonist) vs response) and calculates EC50 values which may be reported in pM. A minimum of two replicates is measured for each sample. The reported values are averages of the replicates.

    Example 1

    Liraglutide Solubility

    [0285] Solubility of liraglutide was determined using Assay (I) described herein. Liraglutide was prepared using Method 1 (evaporation) or Method 2 (precipitation) as described in subsection “96-well plate preparation”. The results as well as the specific parameters used are shown in Table 3a and Table 3b.

    TABLE-US-00006 TABLE 3a Treatment conditions using Method 2 (precipitation) and results in the form of GLP-1 peptide concentration at specific incubation time. GLP-1 peptide concentration [mg/ml] Organic solvent Conc. Temp. Before removal of outliers After removal of outliers Type [% w/w] pH [° C.] 5 min 180 min 24 h 5 min 180 min 24 h MeCN 0.0 3.00 5 0.08 0.11 0.14 0.1 0.1 0.1 MeCN 0.0 3.64 5 0.36 0.06 0.03 0.4 0.1 0.0 MeCN 0.0 4.27 5 0.53 0.06 0.04 0.5 0.1 0.0 MeCN 0.0 4.93 5 0.71 0.04 0.03 0.7 0.0 0.0 MeCN 0.0 5.57 5 0.49 0.04 0.01 0.5 0.0 0.0 MeCN 0.0 6.22 5 0.18 0.06 0.01 0.2 0.1 0.0 MeCN 0.0 6.86 5 1.39 1.64 1.53 1.4 1.6 1.5 MeCN 0.0 7.46 5 2.37 >4.0 >4.0 3.7 >4.0 >4.0 MeCN 6.4 3.00 5 0.08 0.11 0.08 0.1 0.1 0.1 MeCN 6.4 3.64 5 0.14 0.04 0.04 0.1 0.0 0.0 MeCN 6.4 4.27 5 0.22 0.07 0.06 0.2 0.1 0.1 MeCN 6.4 4.93 5 0.14 0.06 0.04 0.1 0.1 0.0 MeCN 6.4 5.57 5 0.12 0.04 0.03 0.1 0.0 0.0 MeCN 6.4 6.22 5 0.08 0.08 0.01 0.1 0.1 0.0 MeCN 6.4 6.86 5 1.40 2.30 2.30 1.4 2.3 2.3 MeCN 6.4 7.46 5 2.39 >4.0 3.87 3.7 >4.0 >4.0 MeCN 12.7 3.00 5 0.08 0.12 0.12 0.1 0.1 0.1 MeCN 12.7 3.64 5 0.06 0.04 0.01 0.1 0.0 0.0 MeCN 12.7 4.27 5 0.07 0.04 0.04 0.1 0.0 0.0 MeCN 12.7 4.93 5 0.07 0.04 0.01 0.1 0.0 0.0 MeCN 12.7 5.57 5 0.08 0.06 0.03 0.1 0.1 0.0 MeCN 12.7 6.22 5 0.22 0.15 0.08 0.2 0.2 0.1 MeCN 12.7 6.86 5 1.93 >4.0 >4.0 1.9 >4.0 >4.0 MeCN 12.7 7.46 5 2.00 >4.0 >4.0 2.7 >4.0 4.0 MeCN 19.1 3.00 5 0.85 0.74 0.67 0.8 0.7 0.7 MeCN 19.1 3.64 5 0.08 0.07 0.04 0.1 0.1 0.0 MeCN 19.1 4.27 5 0.06 0.06 0.04 0.1 0.1 0.0 MeCN 19.1 4.93 5 0.07 0.04 0.03 0.1 0.0 0.0 MeCN 19.1 5.57 5 0.07 0.06 0.06 0.1 0.1 0.1 MeCN 19.1 6.22 5 0.90 0.75 0.39 0.9 0.7 0.4 MeCN 19.1 6.86 5 1.53 >4.0 >4.0 1.5 >4.0 >4.0 MeCN 19.1 7.46 5 1.65 >4.0 >4.0 1.9 >4.0 3.2 MeCN 25.5 3.00 5 1.71 3.69 >4.0 1.7 3.7 >4.0 MeCN 25.5 3.64 5 0.07 0.07 0.04 0.1 0.1 0.0 MeCN 25.5 4.27 5 0.06 0.06 0.04 0.1 0.1 0.0 MeCN 25.5 4.93 5 0.06 0.07 0.04 0.1 0.1 0.0 MeCN 25.5 5.57 5 0.11 0.07 0.08 0.1 0.1 0.1 MeCN 25.5 6.22 5 0.49 0.92 0.40 0.5 0.9 0.4 MeCN 25.5 6.86 5 1.58 2.69 2.43 1.6 2.7 2.4 MeCN 25.5 7.46 5 2.85 >4.0 >4.0 2.7 >4.0 2.4 MeCN 31.8 3.00 5 1.74 3.93 3.61 1.7 3.9 3.6 MeCN 31.8 3.64 5 0.19 0.08 0.07 0.2 0.1 0.1 MeCN 31.8 4.27 5 0.07 0.08 0.10 0.1 0.1 0.1 MeCN 31.8 4.93 5 0.06 0.07 0.04 0.1 0.1 0.0 MeCN 31.8 5.57 5 0.25 0.18 0.10 0.2 0.2 0.1 MeCN 31.8 6.22 5 0.46 0.53 0.39 0.5 0.5 0.4 MeCN 31.8 6.86 5 0.89 1.43 1.19 0.9 1.4 1.2 MeCN 31.8 7.46 5 2.12 3.94 3.47 2.7 3.1 2.2 MeCN 38.2 3.00 5 1.24 2.72 2.62 1.2 2.7 2.6 MeCN 38.2 3.64 5 0.29 0.26 0.11 0.3 0.3 0.1 MeCN 38.2 4.27 5 0.21 0.15 0.12 0.2 0.2 0.1 MeCN 38.2 4.93 5 0.18 0.12 0.07 0.2 0.1 0.1 MeCN 38.2 5.57 5 0.25 0.31 0.24 0.2 0.3 0.2 MeCN 38.2 6.22 5 0.35 0.42 0.37 0.3 0.4 0.4 MeCN 38.2 6.86 5 0.83 1.12 1.15 0.8 1.1 1.2 MeCN 38.2 7.46 5 1.50 2.86 2.37 2.3 3.8 3.1 MeCN 44.5 3.00 5 1.06 1.35 1.08 1.1 1.3 1.1 MeCN 44.5 3.64 5 0.31 0.37 0.17 0.3 0.4 0.2 MeCN 44.5 4.27 5 0.22 0.32 0.11 0.2 0.3 0.1 MeCN 44.5 4.93 5 0.25 0.21 0.17 0.2 0.2 0.2 MeCN 44.5 5.57 5 0.24 0.28 0.29 0.2 0.3 0.3 MeCN 44.5 6.22 5 0.42 0.50 0.54 0.4 0.5 0.5 MeCN 44.5 6.86 5 0.58 1.00 1.03 0.6 1.0 1.0 MeCN 44.5 7.46 5 0.68 1.99 1.19 1.5 2.7 3.2 MeCN 50.9 3.00 5 0.94 0.85 0.62 0.9 0.8 0.6 MeCN 50.9 3.64 5 0.28 0.47 0.37 0.3 0.5 0.4 MeCN 50.9 4.27 5 0.18 0.28 0.22 0.2 0.3 0.2 MeCN 50.9 4.93 5 0.26 0.33 0.28 0.3 0.3 0.3 MeCN 50.9 5.57 5 0.26 0.40 0.36 0.3 0.4 0.4 MeCN 50.9 6.22 5 0.32 0.47 0.44 0.3 0.5 0.4 MeCN 50.9 6.86 5 0.36 0.65 0.81 0.4 0.7 0.8 MeCN 50.9 7.46 5 0.44 0.94 1.26 2.2 1.8 2.5 MeCN 57.3 3.00 5 1.32 1.07 0.33 1.3 1.1 0.3 MeCN 57.3 3.64 5 0.36 0.47 0.51 0.4 0.5 0.5 MeCN 57.3 4.27 5 0.26 0.39 0.47 0.3 0.4 0.5 MeCN 57.3 4.93 5 0.19 0.31 0.36 0.2 0.3 0.4 MeCN 57.3 5.57 5 0.17 0.29 0.40 0.2 0.3 0.4 MeCN 57.3 6.22 5 0.22 0.40 0.46 0.2 0.4 0.5 MeCN 57.3 6.86 5 0.32 0.57 0.74 0.3 0.6 0.7 MeCN 57.3 7.46 5 0.29 0.69 1.19 1.1 2.2 3.2 MeCN 63.6 3.00 5 1.22 1.29 0.40 1.2 1.3 0.4 MeCN 63.6 3.64 5 0.32 0.54 0.67 0.3 0.5 0.7 MeCN 63.6 4.27 5 0.24 0.37 0.39 0.2 0.4 0.4 MeCN 63.6 4.93 5 0.21 0.29 0.42 0.2 0.3 0.4 MeCN 63.6 5.57 5 0.25 0.37 0.51 0.2 0.4 0.5 MeCN 63.6 6.22 5 0.19 0.33 0.44 0.2 0.3 0.4 MeCN 63.6 6.86 5 0.29 0.54 0.72 0.3 0.5 0.7 MeCN 63.6 7.46 5 0.25 0.60 0.85 0.9 1.0 2.4 MeCN 70.0 3.00 5 1.32 1.87 1.03 1.3 1.9 1.0 MeCN 70.0 3.64 5 0.32 0.54 0.68 0.3 0.5 0.7 MeCN 70.0 4.27 5 0.22 0.39 0.46 0.2 0.4 0.5 MeCN 70.0 4.93 5 0.19 0.26 0.35 0.2 0.3 0.3 MeCN 70.0 5.57 5 0.21 0.36 0.50 0.2 0.4 0.5 MeCN 70.0 6.22 5 0.18 0.32 0.43 0.2 0.3 0.4 MeCN 70.0 6.86 5 0.29 0.51 0.72 0.3 0.5 0.7 MeCN 70.0 7.46 5 0.28 0.56 0.78 0.9 0.7 1.6 MeCN 0.0 7.50 5 2.2 >4.0 >4.0 MeCN 0.0 8.00 5 2.5 3.8 >4.0 2.5 3.8 >4.0 MeCN 0.0 8.50 5 3.5 >4.0 >4.0 3.5 >4.0 >4.0 MeCN 0.0 9.00 5 3.2 3.9 >4.0 3.2 3.9 >4.0 MeCN 0.0 9.50 5 3.3 >4.0 >4.0 3.3 >4.0 >4.0 MeCN 0.0 10.00 5 3.0 >4.0 >4.0 3.0 >4.0 >4.0 MeCN 0.0 10.50 5 3.3 >4.0 >4.0 3.3 >4.0 >4.0 MeCN 0.0 11.00 5 2.9 >4.0 >4.0 2.9 >4.0 >4.0 MeCN 6.4 7.50 5 2.7 >4.0 >4.0 MeCN 6.4 8.00 5 3.1 >4.0 >4.0 3.1 >4.0 >4.0 MeCN 6.4 8.50 5 3.2 >4.0 >4.0 3.2 >4.0 >4.0 MeCN 6.4 9.00 5 3.1 >4.0 >4.0 3.1 >4.0 >4.0 MeCN 6.4 9.50 5 2.9 >4.0 >4.0 2.9 >4.0 >4.0 MeCN 6.4 10.00 5 3.1 >4.0 >4.0 3.1 >4.0 >4.0 MeCN 6.4 10.50 5 3.7 >4.0 >4.0 3.7 >4.0 >4.0 MeCN 6.4 11.00 5 2.9 >4.0 >4.0 2.9 >4.0 >4.0 MeCN 12.7 7.50 5 2.9 >4.0 4.0 MeCN 12.7 8.00 5 2.9 >4.0 >4.0 2.9 >4.0 >4.0 MeCN 12.7 8.50 5 3.1 >4.0 >4.0 3.1 >4.0 >4.0 MeCN 12.7 9.00 5 2.4 >4.0 3.7 2.4 >4.0 3.7 MeCN 12.7 9.50 5 2.6 >4.0 >4.0 2.6 >4.0 >4.0 MeCN 12.7 10.00 5 2.5 >4.0 >4.0 2.5 >4.0 >4.0 MeCN 12.7 10.50 5 3.3 >4.0 >4.0 3.3 >4.0 >4.0 MeCN 12.7 11.00 5 2.8 >4.0 >4.0 2.8 >4.0 >4.0 MeCN 19.1 7.50 5 1.9 >4.0 3.2 MeCN 19.1 8.00 5 1.7 >4.0 >4.0 1.7 >4.0 >4.0 MeCN 19.1 8.50 5 1.9 >4.0 >4.0 1.9 >4.0 >4.0 MeCN 19.1 9.00 5 1.7 >4.0 >4.0 1.7 >4.0 >4.0 MeCN 19.1 9.50 5 1.9 >4.0 >4.0 1.9 >4.0 >4.0 MeCN 19.1 10.00 5 1.7 >4.0 >4.0 1.7 >4.0 >4.0 MeCN 19.1 10.50 5 1.9 >4.0 >4.0 1.9 >4.0 >4.0 MeCN 19.1 11.00 5 1.8 3.9 >4.0 1.8 3.9 >4.0 MeCN 25.5 7.50 5 1.7 >4.0 2.4 MeCN 25.5 8.00 5 1.2 >4.0 4.0 1.2 >4.0 4.0 MeCN 25.5 8.50 5 1.0 >4.0 >4.0 1.0 >4.0 >4.0 MeCN 25.5 9.00 5 1.0 3.5 4.0 1.0 3.5 4.0 MeCN 25.5 9.50 5 3.2 >4.0 >4.0 3.2 >4.0 >4.0 MeCN 25.5 10.00 5 0.8 3.2 >4.0 0.8 3.2 >4.0 MeCN 25.5 10.50 5 1.1 >4.0 >4.0 1.1 >4.0 >4.0 MeCN 25.5 11.00 5 2.6 >4.0 >4.0 2.6 >4.0 >4.0 MeCN 31.8 7.50 5 0.9 3.1 2.2 MeCN 31.8 8.00 5 0.8 3.2 3.2 0.8 3.2 3.2 MeCN 31.8 8.50 5 0.9 >4.0 >4.0 0.9 >4.0 >4.0 MeCN 31.8 9.00 5 0.5 3.4 >4.0 0.5 3.4 >4.0 MeCN 31.8 9.50 5 0.7 >4.0 >4.0 0.7 >4.0 >4.0 MeCN 31.8 10.00 5 0.8 >4.0 >4.0 0.8 >4.0 >4.0 MeCN 31.8 10.50 5 1.1 >4.0 >4.0 1.1 >4.0 >4.0 MeCN 31.8 11.00 5 0.8 3.9 >4.0 0.8 3.9 >4.0 MeCN 38.2 7.50 5 0.8 3.8 3.1 MeCN 38.2 8.00 5 0.7 3.0 3.7 0.7 3.0 3.7 MeCN 38.2 8.50 5 0.7 >4.0 3.9 0.7 >4.0 3.9 MeCN 38.2 9.00 5 0.6 >4.0 >4.0 0.6 >4.0 >4.0 MeCN 38.2 9.50 5 0.7 >4.0 >4.0 0.7 >4.0 >4.0 MeCN 38.2 10.00 5 0.7 >4.0 >4.0 0.7 >4.0 >4.0 MeCN 38.2 10.50 5 0.7 3.7 >4.0 0.7 3.7 >4.0 MeCN 38.2 11.00 5 0.8 >4.0 3.2 0.8 >4.0 3.2 MeCN 44.5 7.50 5 0.5 2.7 3.2 MeCN 44.5 8.00 5 0.4 2.7 3.4 0.4 2.7 3.4 MeCN 44.5 8.50 5 0.8 >4.0 2.0 0.8 >4.0 2.0 MeCN 44.5 9.00 5 0.4 >4.0 >4.0 0.4 >4.0 >4.0 MeCN 44.5 9.50 5 0.6 3.8 >4.0 0.6 3.8 >4.0 MeCN 44.5 10.00 5 0.5 >4.0 >4.0 0.5 >4.0 >4.0 MeCN 44.5 10.50 5 0.7 >4.0 >4.0 0.7 >4.0 >4.0 MeCN 44.5 11.00 5 0.4 >4.0 >4.0 0.4 >4.0 >4.0 MeCN 50.9 7.50 5 0.6 1.8 2.5 MeCN 50.9 8.00 5 0.8 3.0 3.7 0.8 3.0 3.7 MeCN 50.9 8.50 5 0.8 >4.0 1.5 0.8 >4.0 1.5 MeCN 50.9 9.00 5 0.6 3.9 2.4 0.6 3.9 2.4 MeCN 50.9 9.50 5 0.7 >4.0 3.9 0.7 >4.0 3.9 MeCN 50.9 10.00 5 0.5 3.9 >4.0 0.5 3.9 >4.0 MeCN 50.9 10.50 5 0.7 >4.0 3.9 0.7 >4.0 3.9 MeCN 50.9 11.00 5 0.6 >4.0 >4.0 0.6 >4.0 >4.0 MeCN 57.3 7.50 5 0.6 2.2 3.2 MeCN 57.3 8.00 5 0.7 2.4 3.7 0.7 2.4 3.7 MeCN 57.3 8.50 5 0.6 3.3 2.5 0.6 3.3 2.5 MeCN 57.3 9.00 5 0.6 3.4 1.4 0.6 3.4 1.4 MeCN 57.3 9.50 5 0.5 >4.0 2.5 0.5 >4.0 2.5 MeCN 57.3 10.00 5 0.4 >4.0 1.1 0.4 >4.0 1.1 MeCN 57.3 10.50 5 0.5 >4.0 1.7 0.5 >4.0 1.7 MeCN 57.3 11.00 5 0.5 >4.0 3.6 0.5 >4.0 3.6 MeCN 63.6 7.50 5 0.4 1.0 2.4 MeCN 63.6 8.00 5 0.5 1.2 3.2 0.5 1.2 3.2 MeCN 63.6 8.50 5 0.5 3.1 3.1 0.5 3.1 3.1 MeCN 63.6 9.00 5 0.5 1.7 >4.0 0.5 1.7 >4.0 MeCN 63.6 9.50 5 0.6 2.9 1.2 0.6 2.9 1.2 MeCN 63.6 10.00 5 0.4 2.9 1.0 0.4 2.9 1.0 MeCN 63.6 10.50 5 0.6 3.4 1.3 0.6 3.4 1.3 MeCN 63.6 11.00 5 0.5 3.2 1.0 0.5 3.2 1.0 MeCN 70.0 7.50 5 0.3 0.7 1.6 MeCN 70.0 8.00 5 0.4 1.0 2.5 0.4 1.0 2.5 MeCN 70.0 8.50 5 0.4 1.4 3.3 0.4 1.4 3.3 MeCN 70.0 9.00 5 0.4 1.5 >4.0 0.4 1.5 >4.0 MeCN 70.0 9.50 5 0.5 1.9 >4.0 0.5 1.9 >4.0 MeCN 70.0 10.00 5 0.4 2.4 1.0 0.4 2.4 1.0 MeCN 70.0 10.50 5 0.6 3.1 1.2 0.6 3.1 1.2 MeCN 70.0 11.00 5 0.6 3.5 1.2 0.6 3.5 1.2 Conc.: Concentration. Temp.: Temperature. n.d.: not determined.

    TABLE-US-00007 TABLE 3b Treatment conditions using Method 1 (evaporation) and results in the form of GLP-1 peptide concentration at specific incubation time. Organic solvent Peptide concentration [mg/ml] Conc. Temp. after after after Type [% w/w] pH [° C.] 5 min 180 min 24 h MeCN 0.0 3.0  5° C. 0.1 0.1 0.2 MeCN 0.0 3.6  5° C. 0.0 0.1 0.1 MeCN 0.0 4.3  5° C. 0.1 0.1 0.2 MeCN 0.0 4.9  5° C. 0.2 0.1 0.1 MeCN 0.0 5.6  5° C. 0.1 0.1 0.1 MeCN 0.0 6.2  5° C. 0.1 0.1 0.1 MeCN 0.0 6.9  5° C. 0.4 2.0 >4.0 MeCN 0.0 7.5  5° C. 0.6 2.6 >4.0 MeCN 6.4 3.0  5° C. 0.1 0.2 0.3 MeCN 6.4 3.6  5° C. 0.1 0.1 0.2 MeCN 6.4 4.3  5° C. 0.1 0.1 0.2 MeCN 6.4 4.9  5° C. 0.1 0.1 0.2 MeCN 6.4 5.6  5° C. 0.1 0.1 0.1 MeCN 6.4 6.2  5° C. 0.1 0.2 0.2 MeCN 6.4 6.9  5° C. 0.8 1.9 >4.0 MeCN 6.4 7.5  5° C. 1.1 2.8 >4.0 MeCN 12.7 3.0  5° C. 0.2 0.2 0.3 MeCN 12.7 3.6  5° C. 0.1 0.2 0.2 MeCN 12.7 4.3  5° C. 0.1 0.1 0.1 MeCN 12.7 4.9  5° C. 0.1 0.1 0.1 MeCN 12.7 5.6  5° C. 0.1 0.1 0.1 MeCN 12.7 6.2  5° C. 0.2 0.3 0.4 MeCN 12.7 6.9  5° C. 1.0 2.3 >4.0 MeCN 12.7 7.5  5° C. 1.3 2.3 >4.0 MeCN 19.1 3.0  5° C. 0.7 1.4 1.5 MeCN 19.1 3.6  5° C. 0.1 0.2 0.2 MeCN 19.1 4.3  5° C. 0.1 0.1 0.1 MeCN 19.1 4.9  5° C. 0.1 0.1 0.2 MeCN 19.1 5.6  5° C. 0.2 0.1 0.2 MeCN 19.1 6.2  5° C. 0.7 0.6 0.4 MeCN 19.1 6.9  5° C. 2.5 >4.0 >4.0 MeCN 19.1 7.5  5° C. 1.4 2.9 >4.0 MeCN 25.5 3.0  5° C. 0.4 0.7 0.7 MeCN 25.5 3.6  5° C. 0.2 0.2 0.2 MeCN 25.5 4.3  5° C. 0.3 0.2 0.1 MeCN 25.5 4.9  5° C. 0.1 0.2 0.1 MeCN 25.5 5.6  5° C. 0.1 0.1 0.1 MeCN 25.5 6.2  5° C. 1.6 0.9 0.2 MeCN 25.5 6.9  5° C. 1.3 3.5 >4.0 MeCN 25.5 7.5  5° C. 1.3 3.8 >4.0 MeCN 31.8 3.0  5° C. 1.0 0.7 0.5 MeCN 31.8 3.6  5° C. 0.1 0.3 0.2 MeCN 31.8 4.3  5° C. 0.2 0.3 0.2 MeCN 31.8 4.9  5° C. 0.1 0.2 0.1 MeCN 31.8 5.6  5° C. 0.3 0.3 0.1 MeCN 31.8 6.2  5° C. 1.7 1.1 0.2 MeCN 31.8 6.9  5° C. 0.9 3.0 2.7 MeCN 31.8 7.5  5° C. 1.1 3.4 >4.0 MeCN 38.2 3.0  5° C. 1.0 1.4 0.5 MeCN 38.2 3.6  5° C. 0.2 0.5 0.5 MeCN 38.2 4.3  5° C. 0.2 0.3 0.2 MeCN 38.2 4.9  5° C. 0.1 0.3 0.2 MeCN 38.2 5.6  5° C. 0.6 0.6 0.2 MeCN 38.2 6.2  5° C. 1.2 1.1 0.4 MeCN 38.2 6.9  5° C. 1.2 2.6 1.6 MeCN 38.2 7.5  5° C. 1.1 4.0 >4.0 MeCN 44.5 3.0  5° C. 0.4 1.4 0.7 MeCN 44.5 3.6  5° C. 0.2 0.6 0.5 MeCN 44.5 4.3  5° C. 0.2 0.3 0.3 MeCN 44.5 4.9  5° C. 0.2 0.3 0.3 MeCN 44.5 5.6  5° C. 0.2 0.6 0.3 MeCN 44.5 6.2  5° C. 1.1 1.4 1.1 MeCN 44.5 6.9  5° C. 1.4 2.0 1.9 MeCN 44.5 7.5  5° C. 1.7 >4.0 >4.0 MeCN 50.9 3.0  5° C. 0.8 1.6 1.7 MeCN 50.9 3.6  5° C. 0.2 0.5 0.7 MeCN 50.9 4.3  5° C. 0.2 0.3 0.4 MeCN 50.9 4.9  5° C. 0.3 0.4 0.3 MeCN 50.9 5.6  5° C. 0.4 0.7 0.6 MeCN 50.9 6.2  5° C. 0.6 0.9 0.9 MeCN 50.9 6.9  5° C. 0.6 1.4 1.7 MeCN 50.9 7.5  5° C. 1.0 3.0 >4.0 MeCN 57.3 3.0  5° C. 0.7 1.2 1.5 MeCN 57.3 3.6  5° C. 0.2 0.5 0.7 MeCN 57.3 4.3  5° C. 0.2 0.4 0.5 MeCN 57.3 4.9  5° C. 0.2 0.4 0.4 MeCN 57.3 5.6  5° C. 0.3 0.6 0.7 MeCN 57.3 6.2  5° C. 0.6 0.7 0.7 MeCN 57.3 6.9  5° C. 0.3 0.6 1.1 MeCN 57.3 7.5  5° C. 1.6 2.3 2.9 MeCN 63.6 3.0  5° C. 0.4 0.7 1.2 MeCN 63.6 3.6  5° C. 0.2 0.4 0.7 MeCN 63.6 4.3  5° C. 0.2 0.4 0.6 MeCN 63.6 4.9  5° C. 0.2 0.4 0.5 MeCN 63.6 5.6  5° C. 0.3 0.4 0.6 MeCN 63.6 6.2  5° C. 0.2 0.4 0.6 MeCN 63.6 6.9  5° C. 0.2 0.4 0.6 MeCN 63.6 7.5  5° C. 0.4 0.5 1.6 MeCN 70.0 3.0  5° C. 0.4 0.5 1.0 MeCN 70.0 3.6  5° C. 0.2 0.4 0.6 MeCN 70.0 4.3  5° C. 0.2 0.3 0.5 MeCN 70.0 4.9  5° C. 0.2 0.3 0.5 MeCN 70.0 5.6  5° C. 0.2 0.3 0.4 MeCN 70.0 6.2  5° C. 0.2 0.3 0.5 MeCN 70.0 6.9  5° C. 0.2 0.3 0.5 MeCN 70.0 7.5  5° C. 0.3 0.4 0.8 MeCN 0.0 8.0  5° C. 0.5 2.1 >4.0 MeCN 0.0 8.5  5° C. 0.3 2.9 >4.0 MeCN 0.0 9.0  5° C. 0.3 2.8 >4.0 MeCN 0.0 9.5  5° C. 0.4 2.6 >4.0 MeCN 0.0 10.0  5° C. 0.4 3.1 >4.0 MeCN 0.0 10.5  5° C. 0.5 2.9 >4.0 MeCN 0.0 11.0  5° C. 0.2 1.6 >4.0 MeCN 6.4 8.0  5° C. 0.8 2.2 >4.0 MeCN 6.4 8.5  5° C. 0.8 2.6 >4.0 MeCN 6.4 9.0  5° C. 1.0 2.9 >4.0 MeCN 6.4 9.5  5° C. 0.6 2.5 >4.0 MeCN 6.4 10.0  5° C. 1.0 3.1 >4.0 MeCN 6.4 10.5  5° C. 0.7 2.6 >4.0 MeCN 6.4 11.0  5° C. 0.7 1.7 >4.0 MeCN 12.7 8.0  5° C. 1.3 2.2 >4.0 MeCN 12.7 8.5  5° C. 0.8 2.1 >4.0 MeCN 12.7 9.0  5° C. 0.8 1.8 >4.0 MeCN 12.7 9.5  5° C. 0.9 1.9 >4.0 MeCN 12.7 10.0  5° C. 0.8 2.3 >4.0 MeCN 12.7 10.5  5° C. 1.1 2.1 >4.0 MeCN 12.7 11.0  5° C. 0.6 1.5 >4.0 MeCN 19.1 8.0  5° C. 1.0 2.7 >4.0 MeCN 19.1 8.5  5° C. 1.2 2.5 >4.0 MeCN 19.1 9.0  5° C. 0.9 2.3 >4.0 MeCN 19.1 9.5  5° C. 1.1 3.3 >4.0 MeCN 19.1 10.0  5° C. 1.4 3.8 >4.0 MeCN 19.1 10.5  5° C. 1.4 >4.0 >4.0 MeCN 19.1 11.0  5° C. 1.0 2.6 >4.0 MeCN 25.5 8.0  5° C. 1.1 3.2 >4.0 MeCN 25.5 8.5  5° C. 1.4 3.5 >4.0 MeCN 25.5 9.0  5° C. 0.5 >4.0 >4.0 MeCN 25.5 9.5  5° C. 1.2 >4.0 >4.0 MeCN 25.5 10.0  5° C. 1.4 3.4 >4.0 MeCN 25.5 10.5  5° C. 1.5 3.8 >4.0 MeCN 25.5 11.0  5° C. 1.0 3.1 >4.0 MeCN 31.8 8.0  5° C. 0.9 2.7 >4.0 MeCN 31.8 8.5  5° C. 2.1 3.6 >4.0 MeCN 31.8 9.0  5° C. 0.8 2.7 >4.0 MeCN 31.8 9.5  5° C. 0.9 3.3 >4.0 MeCN 31.8 10.0  5° C. 1.9 >4.0 2.8 MeCN 31.8 10.5  5° C. 1.3 3.9 3.6 MeCN 31.8 11.0  5° C. 0.8 3.0 >4.0 MeCN 38.2 8.0  5° C. 0.8 3.2 >4.0 MeCN 38.2 8.5  5° C. 0.8 2.9 >4.0 MeCN 38.2 9.0  5° C. 0.4 2.0 >4.0 MeCN 38.2 9.5  5° C. 1.1 3.9 4.0 MeCN 38.2 10.0  5° C. 1.5 >4.0 >4.0 MeCN 38.2 10.5  5° C. 1.2 3.2 2.1 MeCN 38.2 11.0  5° C. 0.6 2.7 >4.0 MeCN 44.5 8.0  5° C. 0.7 2.8 >4.0 MeCN 44.5 8.5  5° C. 1.1 3.3 >4.0 MeCN 44.5 9.0  5° C. 1.7 2.7 >4.0 MeCN 44.5 9.5  5° C. 1.1 3.7 1.3 MeCN 44.5 10.0  5° C. 1.3 3.7 >4.0 MeCN 44.5 10.5  5° C. 0.9 2.9 >4.0 MeCN 44.5 11.0  5° C. 0.8 2.9 >4.0 MeCN 50.9 8.0  5° C. 0.6 2.2 >4.0 MeCN 50.9 8.5  5° C. 0.6 2.6 >4.0 MeCN 50.9 9.0  5° C. 0.6 2.0 >4.0 MeCN 50.9 9.5  5° C. 1.0 2.4 >4.0 MeCN 50.9 10.0  5° C. 1.5 2.6 >4.0 MeCN 50.9 10.5  5° C. 0.9 2.1 3.8 MeCN 50.9 11.0  5° C. 0.7 2.2 >4.0 MeCN 57.3 8.0  5° C. 0.5 1.6 3.4 MeCN 57.3 8.5  5° C. 0.5 1.6 3.7 MeCN 57.3 9.0  5° C. 0.5 1.9 >4.0 MeCN 57.3 9.5  5° C. 1.0 2.0 4.0 MeCN 57.3 10.0  5° C. 1.4 1.6 1.8 MeCN 57.3 10.5  5° C. 1.1 1.1 1.6 MeCN 57.3 11.0  5° C. 0.9 1.4 2.6 MeCN 63.6 8.0  5° C. 0.3 0.6 2.0 MeCN 63.6 8.5  5° C. 0.6 0.8 2.1 MeCN 63.6 9.0  5° C. 1.4 0.9 2.6 MeCN 63.6 9.5  5° C. 0.2 0.5 1.4 MeCN 63.6 10.0  5° C. 0.2 0.3 0.7 MeCN 63.6 10.5  5° C. 0.2 0.3 0.6 MeCN 63.6 11.0  5° C. 0.5 0.6 1.3 MeCN 70.0 8.0  5° C. 0.3 0.4 0.6 MeCN 70.0 8.5  5° C. 0.2 0.4 0.7 MeCN 70.0 9.0  5° C. 0.2 0.4 0.9 MeCN 70.0 9.5  5° C. 0.2 0.3 0.5 MeCN 70.0 10.0  5° C. 0.2 0.3 0.4 MeCN 70.0 10.5  5° C. 0.2 0.2 0.4 MeCN 70.0 11.0  5° C. 0.2 0.2 0.5 MeCN 0.0 3.0 RT 0.1 0.1 0.1 MeCN 0.0 3.6 RT 0.1 0.1 0.1 MeCN 0.0 4.3 RT 0.1 0.1 0.0 MeCN 0.0 4.9 RT 0.3 0.1 n.d. MeCN 0.0 5.6 RT 0.2 0.1 0.0 MeCN 0.0 6.2 RT 0.1 0.4 0.5 MeCN 0.0 6.9 RT 0.6 3.1 >4.0 MeCN 0.0 7.5 RT 0.8 3.0 >4.0 MeCN 6.4 3.0 RT 0.2 0.1 0.1 MeCN 6.4 3.6 RT 0.1 0.1 0.1 MeCN 6.4 4.3 RT 0.1 0.1 0.1 MeCN 6.4 4.9 RT 0.1 0.1 0.1 MeCN 6.4 5.6 RT 0.1 0.1 0.1 MeCN 6.4 6.2 RT 0.4 0.9 1.4 MeCN 6.4 6.9 RT 0.9 2.7 >4.0 MeCN 6.4 7.5 RT 1.1 3.1 >4.0 MeCN 12.7 3.0 RT 0.3 0.1 0.1 MeCN 12.7 3.6 RT 0.1 0.1 0.1 MeCN 12.7 4.3 RT 0.1 0.1 0.1 MeCN 12.7 4.9 RT 0.1 0.1 0.0 MeCN 12.7 5.6 RT 0.2 0.2 0.1 MeCN 12.7 6.2 RT 0.5 1.2 1.3 MeCN 12.7 6.9 RT 1.2 2.6 >4.0 MeCN 12.7 7.5 RT 1.4 3.6 >4.0 MeCN 19.1 3.0 RT 1.0 1.6 1.6 MeCN 19.1 3.6 RT 0.1 0.1 0.0 MeCN 19.1 4.3 RT 0.1 0.1 0.0 MeCN 19.1 4.9 RT 0.1 0.1 0.0 MeCN 19.1 5.6 RT 0.6 0.1 0.1 MeCN 19.1 6.2 RT 0.8 0.8 0.8 MeCN 19.1 6.9 RT 1.2 >4.0 >4.0 MeCN 19.1 7.5 RT 1.6 >4.0 >4.0 MeCN 25.5 3.0 RT 0.5 0.4 0.4 MeCN 25.5 3.6 RT 0.2 0.1 0.1 MeCN 25.5 4.3 RT 0.1 0.1 0.1 MeCN 25.5 4.9 RT 0.1 0.1 0.0 MeCN 25.5 5.6 RT 0.6 0.2 0.1 MeCN 25.5 6.2 RT 1.0 0.6 0.2 MeCN 25.5 6.9 RT 1.2 3.5 1.4 MeCN 25.5 7.5 RT 1.4 >4.0 >4.0 MeCN 31.8 3.0 RT 0.4 0.2 0.2 MeCN 31.8 3.6 RT 0.4 0.2 0.1 MeCN 31.8 4.3 RT 0.2 0.1 0.1 MeCN 31.8 4.9 RT 0.1 0.1 0.0 MeCN 31.8 5.6 RT 0.8 0.3 0.1 MeCN 31.8 6.2 RT 1.2 0.6 0.1 MeCN 31.8 6.9 RT 1.0 3.0 1.6 MeCN 31.8 7.5 RT 1.1 >4.0 >4.0 MeCN 38.2 3.0 RT 0.4 0.5 0.1 MeCN 38.2 3.6 RT 0.2 0.3 0.0 MeCN 38.2 4.3 RT 0.3 0.2 0.1 MeCN 38.2 4.9 RT 0.2 0.2 0.0 MeCN 38.2 5.6 RT 0.7 0.5 0.1 MeCN 38.2 6.2 RT 1.1 0.9 0.2 MeCN 38.2 6.9 RT 1.5 2.3 0.6 MeCN 38.2 7.5 RT 1.0 >4.0 >4.0 MeCN 44.5 3.0 RT 0.5 0.9 0.1 MeCN 44.5 3.6 RT 0.3 0.5 0.0 MeCN 44.5 4.3 RT 0.2 0.2 0.1 MeCN 44.5 4.9 RT 0.2 0.2 0.1 MeCN 44.5 5.6 RT 0.5 0.7 0.1 MeCN 44.5 6.2 RT 1.4 1.2 0.7 MeCN 44.5 6.9 RT 0.9 1.9 1.3 MeCN 44.5 7.5 RT 1.3 >4.0 >4.0 MeCN 50.9 3.0 RT 0.6 1.2 0.1 MeCN 50.9 3.6 RT 0.3 0.4 0.4 MeCN 50.9 4.3 RT 0.2 0.3 0.2 MeCN 50.9 4.9 RT 0.2 0.3 0.2 MeCN 50.9 5.6 RT 0.5 0.7 0.4 MeCN 50.9 6.2 RT 0.7 0.8 0.7 MeCN 50.9 6.9 RT 0.6 1.5 0.0 MeCN 50.9 7.5 RT 1.0 >4.0 >4.0 MeCN 57.3 3.0 RT 0.4 1.0 1.3 MeCN 57.3 3.6 RT 0.2 0.4 0.4 MeCN 57.3 4.3 RT 0.2 0.4 0.3 MeCN 57.3 4.9 RT 0.2 0.4 0.2 MeCN 57.3 5.6 RT 0.3 0.6 0.5 MeCN 57.3 6.2 RT 0.5 0.5 0.6 MeCN 57.3 6.9 RT 0.4 0.8 0.9 MeCN 57.3 7.5 RT 0.8 3.0 >4.0 MeCN 63.6 3.0 RT 0.3 0.8 1.1 MeCN 63.6 3.6 RT 0.2 0.3 0.4 MeCN 63.6 4.3 RT 0.2 0.3 0.4 MeCN 63.6 4.9 RT 0.2 0.4 0.3 MeCN 63.6 5.6 RT 0.3 0.4 0.5 MeCN 63.6 6.2 RT 0.3 0.4 0.4 MeCN 63.6 6.9 RT 0.2 0.4 0.5 MeCN 63.6 7.5 RT 0.5 1.6 3.1 MeCN 70.0 3.0 RT 0.4 0.5 0.8 MeCN 70.0 3.6 RT 0.2 0.3 0.4 MeCN 70.0 4.3 RT 0.2 0.3 0.3 MeCN 70.0 4.9 RT 0.2 0.3 0.3 MeCN 70.0 5.6 RT 0.2 0.2 0.3 MeCN 70.0 6.2 RT 0.2 0.3 0.5 MeCN 70.0 6.9 RT 0.2 0.2 0.4 MeCN 70.0 7.5 RT 0.3 0.8 1.9 MeCN 0.0 8.0 RT 0.6 2.5 >4.0 MeCN 0.0 8.5 RT 0.6 3.5 >4.0 MeCN 0.0 9.0 RT 0.7 2.9 >4.0 MeCN 0.0 9.5 RT 0.8 2.8 >4.0 MeCN 0.0 10.0 RT 0.9 3.4 >4.0 MeCN 0.0 10.5 RT 0.8 2.9 >4.0 MeCN 0.0 11.0 RT 0.7 2.2 >4.0 MeCN 6.4 8.0 RT 1.0 2.2 >4.0 MeCN 6.4 8.5 RT 0.9 2.7 >4.0 MeCN 6.4 9.0 RT 0.9 2.5 >4.0 MeCN 6.4 9.5 RT 0.9 2.4 >4.0 MeCN 6.4 10.0 RT 1.0 3.1 >4.0 MeCN 6.4 10.5 RT 0.9 2.8 >4.0 MeCN 6.4 11.0 RT 0.8 2.3 >4.0 MeCN 12.7 8.0 RT 3.2 3.8 >4.0 MeCN 12.7 8.5 RT 0.9 2.6 >4.0 MeCN 12.7 9.0 RT 1.0 2.6 >4.0 MeCN 12.7 9.5 RT 1.1 2.9 >4.0 MeCN 12.7 10.0 RT 1.0 3.3 >4.0 MeCN 12.7 10.5 RT 1.2 3.3 >4.0 MeCN 12.7 11.0 RT 1.0 2.9 >4.0 MeCN 19.1 8.0 RT 1.6 3.9 >4.0 MeCN 19.1 8.5 RT 1.2 3.7 >4.0 MeCN 19.1 9.0 RT 1.0 3.7 >4.0 MeCN 19.1 9.5 RT 1.7 >4.0 >4.0 MeCN 19.1 10.0 RT 1.3 >4.0 >4.0 MeCN 19.1 10.5 RT 1.6 >4.0 >4.0 MeCN 19.1 11.0 RT 1.3 3.6 >4.0 MeCN 25.5 8.0 RT 1.1 3.9 >4.0 MeCN 25.5 8.5 RT 1.0 >4.0 >4.0 MeCN 25.5 9.0 RT 0.5 3.5 >4.0 MeCN 25.5 9.5 RT 1.5 >4.0 >4.0 MeCN 25.5 10.0 RT 1.6 >4.0 >4.0 MeCN 25.5 10.5 RT 1.7 >4.0 >4.0 MeCN 25.5 11.0 RT 1.2 >4.0 >4.0 MeCN 31.8 8.0 RT 0.9 >4.0 >4.0 MeCN 31.8 8.5 RT 1.1 >4.0 >4.0 MeCN 31.8 9.0 RT 1.2 3.8 >4.0 MeCN 31.8 9.5 RT 1.3 >4.0 >4.0 MeCN 31.8 10.0 RT 1.6 >4.0 >4.0 MeCN 31.8 10.5 RT 1.4 >4.0 >4.0 MeCN 31.8 11.0 RT 1.1 >4.0 >4.0 MeCN 38.2 8.0 RT 1.4 >4.0 >4.0 MeCN 38.2 8.5 RT 1.7 >4.0 >4.0 MeCN 38.2 9.0 RT 1.1 >4.0 >4.0 MeCN 38.2 9.5 RT 1.0 >4.0 >4.0 MeCN 38.2 10.0 RT 1.9 >4.0 >4.0 MeCN 38.2 10.5 RT 1.6 >4.0 3.8 MeCN 38.2 11.0 RT 1.2 >4.0 3.4 MeCN 44.5 8.0 RT 1.0 >4.0 >4.0 MeCN 44.5 8.5 RT 1.1 3.9 >4.0 MeCN 44.5 9.0 RT 0.8 3.5 >4.0 MeCN 44.5 9.5 RT 1.0 >4.0 >4.0 MeCN 44.5 10.0 RT 2.0 >4.0 3.7 MeCN 44.5 10.5 RT 1.1 >4.0 4.0 MeCN 44.5 11.0 RT 1.3 >4.0 >4.0 MeCN 50.9 8.0 RT 0.7 3.8 >4.0 MeCN 50.9 8.5 RT 1.0 3.7 >4.0 MeCN 50.9 9.0 RT 0.7 2.8 >4.0 MeCN 50.9 9.5 RT 1.6 >4.0 4.0 MeCN 50.9 10.0 RT 1.9 >4.0 3.9 MeCN 50.9 10.5 RT 1.0 3.7 >4.0 MeCN 50.9 11.0 RT 0.8 >4.0 >4.0 MeCN 57.3 8.0 RT 0.6 2.8 >4.0 MeCN 57.3 8.5 RT 0.5 2.9 >4.0 MeCN 57.3 9.0 RT 0.4 2.2 >4.0 MeCN 57.3 9.5 RT 0.7 3.0 >4.0 MeCN 57.3 10.0 RT 1.0 2.0 >4.0 MeCN 57.3 10.5 RT 0.8 1.6 >4.0 MeCN 57.3 11.0 RT 0.7 2.7 >4.0 MeCN 63.6 8.0 RT 0.3 1.2 3.3 MeCN 63.6 8.5 RT 0.3 1.3 2.9 MeCN 63.6 9.0 RT 0.3 1.5 >4.0 MeCN 63.6 9.5 RT 0.3 1.6 >4.0 MeCN 63.6 10.0 RT 0.4 0.6 1.6 MeCN 63.6 10.5 RT 0.4 0.6 1.8 MeCN 63.6 11.0 RT 0.4 1.6 0.9 MeCN 70.0 8.0 RT 0.2 0.9 1.9 MeCN 70.0 8.5 RT 0.2 0.5 1.6 MeCN 70.0 9.0 RT 0.2 1.0 2.5 MeCN 70.0 9.5 RT 0.2 0.4 1.6 MeCN 70.0 10.0 RT 0.2 0.3 1.0 MeCN 70.0 10.5 RT 0.2 0.3 1.1 MeCN 70.0 11.0 RT 0.2 0.8 2.3 MeCN 0.0 3.0 70° C. 1.0 1.5 n.d. MeCN 0.0 3.6 70° C. 0.0 0.2 n.d. MeCN 0.0 4.3 70° C. 0.1 0.1 n.d. MeCN 0.0 4.9 70° C. 0.9 0.0 n.d. MeCN 0.0 5.6 70° C. 0.3 1.7 n.d. MeCN 0.0 6.2 70° C. 0.8 >4.0 n.d. MeCN 0.0 6.9 70° C. 2.0 >4.0 n.d. MeCN 0.0 7.5 70° C. 1.8 >4.0 n.d. MeCN 6.4 3.0 70° C. 2.2 >4.0 n.d. MeCN 6.4 3.6 70° C. 0.4 0.3 n.d. MeCN 6.4 4.3 70° C. 0.1 0.1 n.d. MeCN 6.4 4.9 70° C. 0.3 0.1 n.d. MeCN 6.4 5.6 70° C. 0.7 1.0 n.d. MeCN 6.4 6.2 70° C. 2.4 >4.0 n.d. MeCN 6.4 6.9 70° C. 3.0 >4.0 n.d. MeCN 6.4 7.5 70° C. 2.5 >4.0 n.d. MeCN 12.7 3.0 70° C. 3.5 >4.0 n.d. MeCN 12.7 3.6 70° C. 0.3 0.1 n.d. MeCN 12.7 4.3 70° C. 0.1 0.0 n.d. MeCN 12.7 4.9 70° C. 0.1 0.1 n.d. MeCN 12.7 5.6 70° C. 0.5 0.1 n.d. MeCN 12.7 6.2 70° C. 1.8 1.3 n.d. MeCN 12.7 6.9 70° C. 3.2 >4.0 n.d. MeCN 12.7 7.5 70° C. 3.7 >4.0 n.d. MeCN 19.1 3.0 70° C. 1.8 1.1 n.d. MeCN 19.1 3.6 70° C. 0.1 0.0 n.d. MeCN 19.1 4.3 70° C. 0.1 0.1 n.d. MeCN 19.1 4.9 70° C. 0.1 0.1 n.d. MeCN 19.1 5.6 70° C. 0.2 0.1 n.d. MeCN 19.1 6.2 70° C. 1.3 0.7 n.d. MeCN 19.1 6.9 70° C. >4.0 >4.0 n.d. MeCN 19.1 7.5 70° C. >4.0 >4.0 n.d. MeCN 25.5 3.0 70° C. 0.6 0.9 n.d. MeCN 25.5 3.6 70° C. 0.1 0.1 n.d. MeCN 25.5 4.3 70° C. 0.1 0.1 n.d. MeCN 25.5 4.9 70° C. 0.1 0.1 n.d. MeCN 25.5 5.6 70° C. 0.2 0.1 n.d. MeCN 25.5 6.2 70° C. 0.9 0.3 n.d. MeCN 25.5 6.9 70° C. 3.8 3.5 n.d. MeCN 25.5 7.5 70° C. >4.0 >4.0 n.d. MeCN 31.8 3.0 70° C. 0.7 1.3 n.d. MeCN 31.8 3.6 70° C. 0.2 0.2 n.d. MeCN 31.8 4.3 70° C. 0.2 0.2 n.d. MeCN 31.8 4.9 70° C. 0.2 0.1 n.d. MeCN 31.8 5.6 70° C. 0.7 0.2 n.d. MeCN 31.8 6.2 70° C. 1.4 0.8 n.d. MeCN 31.8 6.9 70° C. 3.3 3.5 n.d. MeCN 31.8 7.5 70° C. >4.0 >4.0 n.d. MeCN 38.2 3.0 70° C. 0.7 1.1 n.d. MeCN 38.2 3.6 70° C. 0.4 0.6 n.d. MeCN 38.2 4.3 70° C. 0.4 0.3 n.d. MeCN 38.2 4.9 70° C. 0.3 0.3 n.d. MeCN 38.2 5.6 70° C. 1.1 0.8 n.d. MeCN 38.2 6.2 70° C. 1.7 1.4 n.d. MeCN 38.2 6.9 70° C. 2.7 3.8 n.d. MeCN 38.2 7.5 70° C. >4.0 >4.0 n.d. MeCN 44.5 3.0 70° C. 1.2 2.0 n.d. MeCN 44.5 3.6 70° C. 0.5 0.8 n.d. MeCN 44.5 4.3 70° C. 0.5 0.6 n.d. MeCN 44.5 4.9 70° C. 0.4 0.5 n.d. MeCN 44.5 5.6 70° C. 1.1 1.4 n.d. MeCN 44.5 6.2 70° C. 1.8 2.2 n.d. MeCN 44.5 6.9 70° C. 2.7 >4.0 n.d. MeCN 44.5 7.5 70° C. >4.0 >4.0 n.d. MeCN 50.9 3.0 70° C. 1.0 n.d. n.d. MeCN 50.9 3.6 70° C. 0.5 0.9 n.d. MeCN 50.9 4.3 70° C. 0.6 0.9 n.d. MeCN 50.9 4.9 70° C. 0.5 0.9 n.d. MeCN 50.9 5.6 70° C. 1.0 1.5 n.d. MeCN 50.9 6.2 70° C. 1.0 2.0 n.d. MeCN 50.9 6.9 70° C. 2.2 3.6 n.d. MeCN 50.9 7.5 70° C. >4.0 >4.0 n.d. MeCN 57.3 3.0 70° C. 0.9 2.6 n.d. MeCN 57.3 3.6 70° C. 0.5 n.d. n.d. MeCN 57.3 4.3 70° C. 0.5 1.3 n.d. MeCN 57.3 4.9 70° C. 0.6 1.3 n.d. MeCN 57.3 5.6 70° C. 0.9 1.8 n.d. MeCN 57.3 6.2 70° C. 0.9 2.0 n.d. MeCN 57.3 6.9 70° C. 0.9 2.7 n.d. MeCN 57.3 7.5 70° C. 3.3 >4.0 n.d. MeCN 63.6 3.0 70° C. 0.9 2.8 n.d. MeCN 63.6 3.6 70° C. 0.6 n.d. n.d. MeCN 63.6 4.3 70° C. 0.5 1.8 n.d. MeCN 63.6 4.9 70° C. 0.5 1.7 n.d. MeCN 63.6 5.6 70° C. 0.7 1.7 n.d. MeCN 63.6 6.2 70° C. 0.5 2.2 n.d. MeCN 63.6 6.9 70° C. 0.5 2.4 n.d. MeCN 63.6 7.5 70° C. 1.9 >4.0 n.d. MeCN 70.0 3.0 70° C. 0.6 2.9 n.d. MeCN 70.0 3.6 70° C. 0.4 2.5 n.d. MeCN 70.0 4.3 70° C. 0.5 2.4 n.d. MeCN 70.0 4.9 70° C. 0.5 2.4 n.d. MeCN 70.0 5.6 70° C. 0.5 2.6 n.d. MeCN 70.0 6.2 70° C. 0.5 3.7 n.d. MeCN 70.0 6.9 70° C. 0.5 3.6 n.d. MeCN 70.0 7.5 70° C. 0.7 3.3 n.d. MeCN 0.0 8.0 70° C. 2.2 >4.0 n.d. MeCN 0.0 8.5 70° C. 1.9 >4.0 n.d. MeCN 0.0 9.0 70° C. 2.1 >4.0 n.d. MeCN 0.0 9.5 70° C. 2.3 >4.0 n.d. MeCN 0.0 10.0 70° C. 2.2 >4.0 n.d. MeCN 0.0 10.5 70° C. 2.6 >4.0 n.d. MeCN 0.0 11.0 70° C. 2.0 >4.0 n.d. MeCN 6.4 8.0 70° C. 2.3 >4.0 n.d. MeCN 6.4 8.5 70° C. 2.5 >4.0 n.d. MeCN 6.4 9.0 70° C. 2.9 >4.0 n.d. MeCN 6.4 9.5 70° C. 3.2 >4.0 n.d. MeCN 6.4 10.0 70° C. 3.1 >4.0 n.d. MeCN 6.4 10.5 70° C. 3.3 >4.0 n.d. MeCN 6.4 11.0 70° C. 2.5 >4.0 n.d. MeCN 12.7 8.0 70° C. 3.6 >4.0 n.d. MeCN 12.7 8.5 70° C. 3.5 >4.0 n.d. MeCN 12.7 9.0 70° C. 3.5 >4.0 n.d. MeCN 12.7 9.5 70° C. >4.0 >4.0 n.d. MeCN 12.7 10.0 70° C. >4.0 >4.0 n.d. MeCN 12.7 10.5 70° C. >4.0 >4.0 n.d. MeCN 12.7 11.0 70° C. 3.3 >4.0 n.d. MeCN 19.1 8.0 70° C. >4.0 >4.0 n.d. MeCN 19.1 8.5 70° C. >4.0 >4.0 n.d. MeCN 19.1 9.0 70° C. >4.0 >4.0 n.d. MeCN 19.1 9.5 70° C. >4.0 >4.0 n.d. MeCN 19.1 10.0 70° C. >4.0 >4.0 n.d. MeCN 19.1 10.5 70° C. >4.0 >4.0 n.d. MeCN 19.1 11.0 70° C. 3.8 >4.0 n.d. MeCN 25.5 8.0 70° C. >4.0 >4.0 n.d. MeCN 25.5 8.5 70° C. 4.0 >4.0 n.d. MeCN 25.5 9.0 70° C. 3.7 >4.0 n.d. MeCN 25.5 9.5 70° C. >4.0 >4.0 n.d. MeCN 25.5 10.0 70° C. >4.0 >4.0 n.d. MeCN 25.5 10.5 70° C. >4.0 >4.0 n.d. MeCN 25.5 11.0 70° C. >4.0 >4.0 n.d. MeCN 31.8 8.0 70° C. 4.0 >4.0 n.d. MeCN 31.8 8.5 70° C. >4.0 >4.0 n.d. MeCN 31.8 9.0 70° C. >4.0 >4.0 n.d. MeCN 31.8 9.5 70° C. 3.8 >4.0 n.d. MeCN 31.8 10.0 70° C. >4.0 >4.0 n.d. MeCN 31.8 10.5 70° C. >4.0 >4.0 n.d. MeCN 31.8 11.0 70° C. 3.7 >4.0 n.d. MeCN 38.2 8.0 70° C. 3.9 >4.0 n.d. MeCN 38.2 8.5 70° C. >4.0 >4.0 n.d. MeCN 38.2 9.0 70° C. 2.8 >4.0 n.d. MeCN 38.2 9.5 70° C. 4.0 >4.0 n.d. MeCN 38.2 10.0 70° C. >4.0 >4.0 n.d. MeCN 38.2 10.5 70° C. 3.3 >4.0 n.d. MeCN 38.2 11.0 70° C. 3.8 >4.0 n.d. MeCN 44.5 8.0 70° C. 3.5 >4.0 n.d. MeCN 44.5 8.5 70° C. 3.6 >4.0 n.d. MeCN 44.5 9.0 70° C. 2.2 >4.0 n.d. MeCN 44.5 9.5 70° C. >4.0 >4.0 n.d. MeCN 44.5 10.0 70° C. >4.0 >4.0 n.d. MeCN 44.5 10.5 70° C. >4.0 >4.0 n.d. MeCN 44.5 11.0 70° C. 3.9 >4.0 n.d. MeCN 50.9 8.0 70° C. 3.7 >4.0 n.d. MeCN 50.9 8.5 70° C. 2.9 >4.0 n.d. MeCN 50.9 9.0 70° C. 1.8 >4.0 n.d. MeCN 50.9 9.5 70° C. >4.0 >4.0 n.d. MeCN 50.9 10.0 70° C. >4.0 >4.0 n.d. MeCN 50.9 10.5 70° C. 3.9 >4.0 n.d. MeCN 50.9 11.0 70° C. 2.6 >4.0 n.d. MeCN 57.3 8.0 70° C. 3.4 >4.0 n.d. MeCN 57.3 8.5 70° C. 3.7 >4.0 n.d. MeCN 57.3 9.0 70° C. 1.6 >4.0 n.d. MeCN 57.3 9.5 70° C. 4.0 >4.0 n.d. MeCN 57.3 10.0 70° C. 2.5 >4.0 n.d. MeCN 57.3 10.5 70° C. 2.6 >4.0 n.d. MeCN 57.3 11.0 70° C. 3.6 >4.0 n.d. MeCN 63.6 8.0 70° C. 2.0 >4.0 n.d. MeCN 63.6 8.5 70° C. 2.2 >4.0 n.d. MeCN 63.6 9.0 70° C. 1.4 >4.0 n.d. MeCN 63.6 9.5 70° C. 2.9 >4.0 n.d. MeCN 63.6 10.0 70° C. 1.0 >4.0 n.d. MeCN 63.6 10.5 70° C. 0.9 >4.0 n.d. MeCN 63.6 11.0 70° C. 2.4 >4.0 n.d. MeCN 70.0 8.0 70° C. 1.2 3.8 n.d. MeCN 70.0 8.5 70° C. 0.8 3.5 n.d. MeCN 70.0 9.0 70° C. 0.9 >4.0 n.d. MeCN 70.0 9.5 70° C. 1.0 3.4 n.d. MeCN 70.0 10.0 70° C. 0.5 2.9 n.d. MeCN 70.0 10.5 70° C. 0.4 3.3 n.d. MeCN 70.0 11.0 70° C. 0.8 3.4 n.d. DMF 0.0 3.1 RT 0.2 0.2 0.3 DMF 0.0 4.8 RT 0.2 0.2 0.2 DMF 0.0 5.8 RT 0.2 1.1 1.5 DMF 0.0 6.3 RT 0.9 2.4 >4.0 DMF 0.0 6.7 RT 1.0 3.1 2.2 DMF 0.0 6.9 RT 1.1 >4.0 >4.0 DMF 0.0 7.2 RT 0.7 >4.0 >4.0 DMF 0.0 7.5 RT 1.9 >4.0 n.d. DMF 6.4 3.1 RT 0.2 0.3 0.8 DMF 6.4 4.8 RT 0.2 0.4 0.2 DMF 6.4 5.8 RT 0.3 2.9 2.1 DMF 6.4 6.3 RT 0.9 2.5 >4.0 DMF 6.4 6.7 RT 1.2 2.5 >4.0 DMF 6.4 6.9 RT 1.1 3.2 >4.0 DMF 6.4 7.2 RT 1.1 3.0 >4.0 DMF 6.4 7.5 RT 1.8 >4.0 n.d. DMF 12.7 3.1 RT 0.2 0.4 1.2 DMF 12.7 4.8 RT 0.2 0.5 0.3 DMF 12.7 5.8 RT 0.3 3.1 2.3 DMF 12.7 6.3 RT 0.9 2.3 >4.0 DMF 12.7 6.7 RT 1.0 2.0 3.9 DMF 12.7 6.9 RT 1.0 3.0 >4.0 DMF 12.7 7.2 RT 0.9 2.3 >4.0 DMF 12.7 7.5 RT 1.7 >4.0 n.d. DMF 19.1 3.1 RT 0.2 0.4 1.3 DMF 19.1 4.8 RT 0.2 0.5 0.3 DMF 19.1 5.8 RT 0.3 2.6 1.2 DMF 19.1 6.3 RT 0.9 2.0 >4.0 DMF 19.1 6.7 RT 0.8 1.3 2.1 DMF 19.1 6.9 RT 1.0 2.8 >4.0 DMF 19.1 7.2 RT 0.7 2.3 >4.0 DMF 19.1 7.5 RT 2.3 >4.0 n.d. DMF 25.5 3.1 RT 0.2 0.3 1.0 DMF 25.5 4.8 RT 0.2 0.3 0.2 DMF 25.5 5.8 RT 0.4 2.1 1.3 DMF 25.5 6.3 RT 0.7 1.5 >4.0 DMF 25.5 6.7 RT 0.7 1.8 2.7 DMF 25.5 6.9 RT 0.9 2.2 >4.0 DMF 25.5 7.2 RT 0.4 1.7 >4.0 DMF 25.5 7.5 RT 2.7 >4.0 n.d. DMF 31.8 3.1 RT 0.2 0.2 0.6 DMF 31.8 4.8 RT 0.2 0.3 0.3 DMF 31.8 5.8 RT 0.3 1.1 0.8 DMF 31.8 6.3 RT 0.5 0.9 2.6 DMF 31.8 6.7 RT 0.6 1.4 2.0 DMF 31.8 6.9 RT 0.9 1.8 2.2 DMF 31.8 7.2 RT 0.8 1.7 >4.0 DMF 31.8 7.5 RT 2.6 >4.0 n.d. DMF 38.2 3.1 RT 0.2 0.2 0.4 DMF 38.2 4.8 RT 0.2 0.3 0.3 DMF 38.2 5.8 RT 0.5 0.6 0.7 DMF 38.2 6.3 RT 0.5 0.6 1.5 DMF 38.2 6.7 RT 0.7 0.8 1.1 DMF 38.2 6.9 RT 0.5 0.6 0.8 DMF 38.2 7.2 RT 0.6 0.7 1.6 DMF 38.2 7.5 RT 1.5 n.d. n.d. DMF 44.5 3.1 RT 0.2 0.2 0.3 DMF 44.5 4.8 RT 0.2 0.2 0.2 DMF 44.5 5.8 RT 0.4 0.4 0.5 DMF 44.5 6.3 RT 0.3 0.3 0.6 DMF 44.5 6.7 RT 0.4 0.4 0.6 DMF 44.5 6.9 RT 0.4 0.6 0.7 DMF 44.5 7.2 RT 0.4 0.6 1.6 DMF 44.5 7.5 RT 1.8 >4.0 n.d. DMF 50.9 3.1 RT 0.2 0.2 0.3 DMF 50.9 4.8 RT 0.2 0.2 0.2 DMF 50.9 5.8 RT 0.3 0.3 0.2 DMF 50.9 6.3 RT 0.3 0.3 0.5 DMF 50.9 6.7 RT 0.3 0.3 0.4 DMF 50.9 6.9 RT 0.3 0.4 0.5 DMF 50.9 7.2 RT 0.3 0.4 0.7 DMF 50.9 7.5 RT 1.0 >4.0 n.d. DMF 57.3 3.1 RT 0.2 0.2 0.3 DMF 57.3 4.8 RT 0.2 0.2 0.2 DMF 57.3 5.8 RT 0.3 0.3 0.2 DMF 57.3 6.3 RT 0.2 0.3 0.4 DMF 57.3 6.7 RT 0.3 0.3 0.3 DMF 57.3 6.9 RT 0.7 0.4 0.4 DMF 57.3 7.2 RT 0.3 0.4 0.5 DMF 57.3 7.5 RT 1.6 >4.0 n.d. DMF 63.6 3.1 RT 0.3 0.3 0.4 DMF 63.6 4.8 RT 0.2 0.2 0.2 DMF 63.6 5.8 RT 0.2 0.3 0.3 DMF 63.6 6.3 RT 0.2 0.3 0.3 DMF 63.6 6.7 RT 0.3 0.3 0.3 DMF 63.6 6.9 RT 0.3 0.4 0.3 DMF 63.6 7.2 RT 0.4 0.5 0.5 DMF 63.6 7.5 RT 3.4 >4.0 n.d. DMF 70.0 3.1 RT 0.3 0.3 0.4 DMF 70.0 4.8 RT 0.2 0.2 0.3 DMF 70.0 5.8 RT 0.2 0.3 0.4 DMF 70.0 6.3 RT 0.2 0.3 0.3 DMF 70.0 6.7 RT 0.5 0.3 0.3 DMF 70.0 6.9 RT 0.5 0.4 0.4 DMF 70.0 7.2 RT 0.3 0.4 0.4 DMF 70.0 7.5 RT 1.5 >4.0 n.d. DMF 0.0 8.0 RT 2.2 >4.0 n.d. DMF 0.0 8.5 RT 2.0 >4.0 n.d. DMF 0.0 9.0 RT 2.7 >4.0 n.d. DMF 0.0 9.5 RT 2.7 >4.0 n.d. DMF 0.0 10.0 RT 2.6 >4.0 n.d. DMF 0.0 10.5 RT 2.9 >4.0 n.d. DMF 0.0 11.0 RT 2.4 >4.0 n.d. DMF 6.4 8.0 RT 1.6 >4.0 n.d. DMF 6.4 8.5 RT 2.1 >4.0 n.d. DMF 6.4 9.0 RT 2.0 >4.0 n.d. DMF 6.4 9.5 RT 2.2 >4.0 n.d. DMF 6.4 10.0 RT 2.3 >4.0 n.d. DMF 6.4 10.5 RT 2.4 >4.0 n.d. DMF 6.4 11.0 RT 1.9 >4.0 n.d. DMF 12.7 8.0 RT 1.4 >4.0 n.d. DMF 12.7 8.5 RT 1.9 >4.0 n.d. DMF 12.7 9.0 RT 1.9 >4.0 n.d. DMF 12.7 9.5 RT 2.3 >4.0 n.d. DMF 12.7 10.0 RT 2.3 >4.0 n.d. DMF 12.7 10.5 RT 2.7 >4.0 n.d. DMF 12.7 11.0 RT 1.7 >4.0 n.d. DMF 19.1 8.0 RT 1.4 >4.0 n.d. DMF 19.1 8.5 RT 1.8 >4.0 n.d. DMF 19.1 9.0 RT 1.9 >4.0 n.d. DMF 19.1 9.5 RT 2.6 >4.0 n.d. DMF 19.1 10.0 RT 2.4 >4.0 n.d. DMF 19.1 10.5 RT 2.3 >4.0 n.d. DMF 19.1 11.0 RT 1.5 >4.0 n.d. DMF 25.5 8.0 RT 1.7 >4.0 n.d. DMF 25.5 8.5 RT 1.9 >4.0 n.d. DMF 25.5 9.0 RT 1.3 >4.0 n.d. DMF 25.5 9.5 RT 3.1 >4.0 n.d. DMF 25.5 10.0 RT 3.2 >4.0 n.d. DMF 25.5 10.5 RT 2.9 >4.0 n.d. DMF 25.5 11.0 RT 2.0 >4.0 n.d. DMF 31.8 8.0 RT 0.9 3.6 n.d. DMF 31.8 8.5 RT 1.5 >4.0 n.d. DMF 31.8 9.0 RT 0.7 >4.0 n.d. DMF 31.8 9.5 RT 2.5 >4.0 n.d. DMF 31.8 10.0 RT 3.3 >4.0 n.d. DMF 31.8 10.5 RT 2.3 >4.0 n.d. DMF 31.8 11.0 RT 1.8 3.7 n.d. DMF 38.2 8.0 RT 0.7 >4.0 n.d. DMF 38.2 8.5 RT 1.5 >4.0 n.d. DMF 38.2 9.0 RT 1.1 >4.0 n.d. DMF 38.2 9.5 RT >4.0 >4.0 n.d. DMF 38.2 10.0 RT 3.2 >4.0 n.d. DMF 38.2 10.5 RT 2.9 >4.0 n.d. DMF 38.2 11.0 RT 0.6 >4.0 n.d. DMF 44.5 8.0 RT 1.0 >4.0 n.d. DMF 44.5 8.5 RT 1.8 >4.0 n.d. DMF 44.5 9.0 RT 3.6 3.8 n.d. DMF 44.5 9.5 RT 3.3 >4.0 n.d. DMF 44.5 10.0 RT >4.0 >4.0 n.d. DMF 44.5 10.5 RT 3.0 >4.0 n.d. DMF 44.5 11.0 RT 3.1 3.8 n.d. DMF 50.9 8.0 RT 1.0 >4.0 n.d. DMF 50.9 8.5 RT 2.1 >4.0 n.d. DMF 50.9 9.0 RT 3.2 >4.0 n.d. DMF 50.9 9.5 RT 2.6 >4.0 n.d. DMF 50.9 10.0 RT 3.8 >4.0 n.d. DMF 50.9 10.5 RT 4.0 >4.0 n.d. DMF 50.9 11.0 RT 1.7 >4.0 n.d. DMF 57.3 8.0 RT 1.3 >4.0 n.d. DMF 57.3 8.5 RT 3.3 >4.0 n.d. DMF 57.3 9.0 RT 2.7 >4.0 n.d. DMF 57.3 9.5 RT 2.5 >4.0 n.d. DMF 57.3 10.0 RT 3.1 >4.0 n.d. DMF 57.3 10.5 RT 3.7 >4.0 n.d. DMF 57.3 11.0 RT 2.1 >4.0 n.d. DMF 63.6 8.0 RT 1.6 >4.0 n.d. DMF 63.6 8.5 RT 3.8 >4.0 n.d. DMF 63.6 9.0 RT 3.1 >4.0 n.d. DMF 63.6 9.5 RT 2.9 >4.0 n.d. DMF 63.6 10.0 RT 3.7 >4.0 n.d. DMF 63.6 10.5 RT 3.5 >4.0 n.d. DMF 63.6 11.0 RT 1.3 >4.0 n.d. DMF 70.0 8.0 RT 1.2 >4.0 n.d. DMF 70.0 8.5 RT 2.9 >4.0 n.d. DMF 70.0 9.0 RT 2.6 >4.0 n.d. DMF 70.0 9.5 RT 3.2 >4.0 n.d. DMF 70.0 10.0 RT 3.4 >4.0 n.d. DMF 70.0 10.5 RT 3.5 >4.0 n.d. DMF 70.0 11.0 RT 1.1 >4.0 n.d. Conc.: Concentration. Temp.: Temperature. n.d.: not determined.

    [0286] The results in Table 3a and 3b show that at certain conditions the presence of organic solvent increases the amount of dissolved GLP-1 peptide.

    [0287] The terms “organic solvent” or “modifier” as used herein means organic solvent.

    [0288] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.