Optimization of poly(glycerol sebacate) synthesis for biomedical

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Optimization of poly(glycerol sebacate) synthesis for biomedical purposes with the Design of Experiments Agnieszka Gadomska-Gajadhur, Micha# Wrzecionek, Grzegorz Matyszczak, Piotr Pi#towski, Micha# Wi#c#aw, and Pawe# Ru#kowski Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00306 • Publication Date (Web): 30 Nov 2018 Downloaded from http://pubs.acs.org on December 6, 2018

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Organic Process Research & Development

Optimization of poly(glycerol sebacate) synthesis for biomedical purposes with the Design of Experiments Agnieszka Gadomska-Gajadhur*, Michał Wrzecionek, Grzegorz Matyszczak, Piotr Piętowski, Michał Więcław and Paweł Ruśkowski Laboratory of Technological Process, Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland.

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Table of Contents

HO OH HO

O

O HO Biomass

+

Polycondensation O 8

H

O

DOE OH

O 8

O

O OR

H

n

poly(glycerol sebacate) for medical purposes


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KEYWORDS: poly (glycerol sebacate), polycondensation, biodegradable polymers, biomedical applications, DOE,

ABSTRACT: Efficient, original synthesis of poly (glycerol sebacate) PGS via polycondensation of glycerine and sebacic acid was achieved. The process was successfully optimized by using BoxBehnken design. PGS was obtained with a high conversion of carboxylic group 89% and very high esterification degree ~82%, containing no catalysts residues. The purification method of prepolymer poly (glycerol sebacate) was developed. Due to the use of biocompatible substrates, obtaining polymer can be used in medical and pharmaceutical application.

INTRODUCTION Polymeric materials are broadly applied for medical purposes.1,2 They are used to make a large number of utility products, e.g. sample containers,3 syringes4 or blood bags.5,6 A particular increase in interest in biodegradable polymers7 has been observed in regenerative medicine8 and pharmacy.9 Biodegradable polymers are used to produce dressing materials10 (including hydrogel ones11,12), resorbable surgical threads,9 bone implants,13 as well as connectors and screws for bonding broken bones.14 Polymeric materials are also used for cell scaffolds to rebuild damaged tissues15 (e.g. cartilage, 16

bone, 17,18 nerve19 or epithelial20 ones). Nowadays intelligent drug delivery systems (DDS),21,22,23,24 projected to achieve long-term therapeutic

effects25 upon a single drug application have become more and more popular

1,26

DDS are aimed to

reduce an amount of medication taken,27,28,29 and consequently, reduce any adverse side effects of therapy.30,31 Although there are a lot of polymers which can be used in medicine, 32,33 due to their different physical34,35 chemical properties,36,37 it is hard to find any to achieve this aim. 38,39 For this reason,


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new polymers40 with better properties41 have constantly been sought or synthesised to fit for specific applications.42,43,44

Scheme 1. Synthesis of poly(glycerol sebacate). O H O

HO OH HO

O

+ HO

T, 24 h OH

8



O H

O

O

O 8

OH OR

n

O

O 8

O

OH O

T, p, 24–168 h

O



O

n

8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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O R = H or sebacyol (–C=O(CH2)8COOH)

H

O

O O

1

2

3

8 O

OH n

4

Poly(glycerol sebacate), PGS (3 or 4) is a very attractive polymer material due to its numerous potential applications.45 It can be used in tissue engineering where it can play the role of cell substrates and scaffolds.46 Due to its unique flexibility and changeability of form, potential rebuilding and regeneration of soft tissues is of particular interest.47,48 It can be used to rebuild the myocardium49,50,51,52 upon micro-damages53,54,55 or necrotic lesions suffered.56 It often acts as a surgical sealer57,58 or tissue adhesive.59,60 PGS can be used to regenerate blood vessels,61,62 the retina63,64,65,66 and nervous tissues.67,68 It is also tested as a material to repair the eardrum.69 Work on the application of PGS for cartilage70,71 and bone regeneration has been in progress.72,73,74 Due to its short degradation time (up to 60 days)75 compared to other biodegradable polyesters, PGS can be used as a medicine carrier.76


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All methods for the preparation of poly(glycerol sebacate) (Scheme 1) are based on the reaction of polycondensation of propane-1,2,3-triol (glycerine, G) (1) (1) with decane-1,2-dioic acid (sebacic acid, SA) (2).45,46,47,77,78,79,80,96 Depending on a degree of its esterification (ED), this polymer has different properties. ED can be controlled through synthesis when under appropriate conditions (reaction time and temperature) (Figure 1).78

Figure 1. The relationship between esterification degree of PGS and the state of polymer (A – brittle opaque wax, B – soft translucent wax, C – viscous translucent liquid, D – soft sticky elastomer, E – nonsticky elastomer)78,81 The synthesis of PGS is most often conducted in two stages45,46,47,77,78,79,80 and leads to a crosslinked polymer (elastomer, Figure 1, D or E),78 which, due to its insolubility in organic solvents, is difficult to further process into a medical product.81


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All the methods of PGS preparation are based on polycondensation in bulk under inert gas (Table 1).45,46,47 Sebacic acid (2) gets dissolved in glycerine (1),82 and then most often heats up to 120– 130 °C for 24–48 h77,78,79,80 to form a poly(glycerol sebacate) prepolymer (3).89 This prepolymer can be stored at room temperature83 as a solution in THF, acetone, methanol.84 With no solvents added it is unstable under storage conditions and gets autocatalyzed degradation by unreacted monomers.85 To date, no research team has been able to obtain a PGS prepolymer purified off unreacted monomers in solid form, which could be stored for a longer period of time.


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Table 1. Literature conditions of poly (glycerol sebacate) synthesis Poly (glycerol sebacate) synthesis I step (prepolymer synthesis) 3

II step (elastomer synthesis) 4

No. Ref.

molar ratio molar ratio G/SA

other conditions

other conditions G/SA

1

1:1

120 °C; 24 h; argon

na

120 °C; 0,1 MPa, 48 h; argon

45

1) 130 °C; 1 kPa; nitrogen 2

1:1

130 °C; 1 kPa; nitrogen

2:2,5

2) 130 °C; 15 MPa; nitrogen

77

3) cooling down to rT 3

1:1

120 °C; 24 h; argon

na

120 °C; 40 mTorr, 48 h; argon

47

4

1:1

120 °C; 1 Torr; 24 h; nitrogen

na

120 °C; 40 mTorr; 48 h

78

na

120 °C; 48 h; argon, low pressure

80

na

130 °C; 24–168 h;

79

2:1; 1:2; 1:1;

1) 120 °C; 24 h; argon

5 2:3; 2:5

2) 120 °C; 48 h; argon, low pressure

I. 130 °C; 24 h; nitrogen 6

1:1

or II. 130 °C; 8 h; nitrogen


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The aim of this paper was to examine the potential shortening of time in reference to the polycondensation of glycerine97 and sebacic acid leading to the production of such PGS prepolymer (3). In order to determine the optimal conditions and obtain mathematical models for the process, some mathematical methods in the field of planning experiments (the Box-Behnken's plan) was applied. In addition, it was decided to develop a method aimed to purify PGS off unreacted monomer residues. It was also decided to examine the application of infrared spectroscopy to monitor the progress of reactions. The physico-chemical properties of PGS may be determined on the grounds of a level of esterification. Unfortunately, the literature contains very scarce data on the influence of the following reaction parameters, i.e. temperature, molar ratio of reagents and reaction times on polymer esterification, process efficiency and viscosity of post-reaction products. The optimization of glycerine with sebacic acid polycondensation by Design of Experiment was carried out. The Box-Behnken plan for three variables was used. The significance of the coefficients of the regression equation were determined using the Student`s test.86,87,88 The optimal conditions for polycondensation were predicted using the Microsoft Solver add-in was predicted.89,90

EXPERIMENTAL SECTION Commercially available solvents (water, dioxane, isopropanol) and reagent (glycerine 99%, sebacic acid 99,5%) were used without further purification. IR spectra were obtained using a BRUKER ALPHA II Platinum ATR spectrometer (in ATR technics). 1H i 13C NMR spectra were obtained using a Mercury-400BB spectrometry (400 MHz).


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Esterification degree (ED) was calculated on the basis of acid and ester number (Supporting information). The conversion of sebacic acid COOH groups (conv COOH) was calculated on the basis of the loss in mass within the post-reaction mixture (Supporting information). The viscosity of 5% PGS solution in isopropanol was determined by means of a capillary viscometer at 25 °C. Synthesis of prepolymer poly(glycerol sebacate) (3). sebacic acid (15 g, 74.2 mmol), anhydrous glycerine (6.83 g, 74.3 mmol, 8.6 mL) were heated under reflux with stirring argon atmosphere a at 200 rpm for 6 hours. Product as a white solid or transparent syrup was obtained with 90% yields (19.65 g,) and 86% degree of esterification. Purification of prepolymer poly(glycerol sebacate) (3) 15 g of PGS prepolymer, 15 mL of dioxane was stirred for 24 hours. Then the solution was poured into 250 mL distilled water at 5 °C. Upon cooling, the suspension was seeped on the cooled Buchner funnel with a double filter. The sediment was dried at 45 °C for 24 hours. Pure prepolymer PGS: white solid; IR (ATR, cm–1): 2929, 1714, 1172, 1039; 1H NMR (400 MHz, CH3Cl-d6) δ/ppm: 1.30 (m, 9H) 1.60 (m, 4H) 2.33 (m, 4H) 3.54 (m, 8H) 4.14 (m, 1H) 5.15 (m, 5H); 13C NMR (100 MHz, CH3Cl-d6) δ/ppm: 24.6; 28.8; 34.1; 63.3; 64.9; 68.2; 70.3; 174.0; 179.1; RESULTS AND DISCUSSION Preliminary study. The polycondensation of glycerine and sebacic acid used in at 2:1 molar ratio (Scheme 1) was examined The reaction was conducted at 140 °C for 6 hours. Due to the planned medical application of the obtained polymer, it was decided to run the process without any catalyst. At the process, the reaction progress was monitored by infrared spectroscopy (Figure 2). Signals at 1720 cm-1 were expanded and shifted towards higher wave numbers, which indicates


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the formation of ester bonds. The disappearance of the acid-originated 1410 cm-1 band and increase in the intensity of the 1185 cm-1 ester band were observed. The kinetics of this reaction was determined on the basis of changes in the intensity of these signals (Figure 3). An intensive increase in the number of ester bonds within the first 45 minutes of the process was found. However, upon 3 hours the reaction was much slower. And upon 5 hours no changes in the signal intensity were observed. On this basis, it was concluded that there is no point in extending the reaction time up to 10 h to obtain the polymer with its higher ester number. It was decided to examine the impact of other process variables making use of the mathematical methods within the scope of experience planning.

Figure 2. IR spectra of synthesis of poly (glycerol sebacate) measured in reaction real time (line: blue – reaction start, red – after 45 min, cyjan – after 3 h; green after 5 h)


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Figure 3. The changes in the intensity of selected infrared signals during the reaction time (line: blue (1410 cm-1) – sebacic acid, green (1185 cm-1) – poly (glycerol sebacate))

Optimization of polycondensation. Poly(glycerol sebacate) for biomedical purposes cannot contain residues of unreacted monomer; thus, it is so important to obtain a high degree of its conversion.90 Depending on the particular application,91 different esterification degrees of PGS are required, so the ability to produce a polymer with a specific ED is very useful.92 Based on preliminary experiments, it was found that important process variables include temperature and reaction time, and glycerine/sebacic acid molar ratio. The significant increase in the viscosity of the reaction mixture observed along with the progress of the reaction made it impossible to control the speed and intensity of mixing. The purpose of optimization was to determine the dependence of esterification degree of poly(glycerol sebacate) (ŷ1) and conversion of carboxylic group (ŷ2) on temperature (z1) and molar ratio glycerine/sebacic acid (z2) and reaction time (z3).93 The reaction below 120 ° C does not take place. For this purpose, a Box-Behnken plan was prepared, enabling the obtaining of the following second degree equation:94


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ŷi = b0 + Σbixi + Σbijxixj + Σbixi2 The optimization criteria were to maximize of esterification degree of poly(glycerol sebacate), ŷ1 and maximize conversion of monomers, ŷ2. We tested the effect of the temperature z1 (130–150 °C), glycerine/sebacic acid molar ratio z2 (1–3) and reaction time z3 (4–6 h) (Table 2, Figure 4).

Figure 4. The “black box” of PGS synthesis: x - optimized variables, u - fixed variables, y experimental results

Table 2. Polycondensation of sebacic acid with glycerine. Box-Behnken design: variables at maximum and minimum levels. zi z1 z2 z3

natural variable temperature (°C) molar ratio glycerine/sebacic acid time (h)

(-1) 130 1 4

(0) 140 2 5

(+1) 150 3 6

A Box-Behnken 15-run design was used, consisting of (1) a 3-level factorial part (twelve runs with three input variables at all combinations of the +1, 0 and –1 levels), and (2) replicates at the centre of the design (three runs with all three variables at 0). All of the other variables were held constant (standard conditions) (Table 3). The experiments were performed in a random order, and


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for each experiment all three of the response variables, yi, were measured. Table 2 shows the design matrix along with the measured responses. To shorten the discussion, the details of statistical analysis are not presented in this paper. We present here only the selected quadratic models (without insignificant coefficients) and the most important diagrams.

Table 3. Polycondensation of sebacic acid with glycerine. Box-Behnken design: experimental matrixa and resultsb

Coded variables

no.

Conversion of COOH (%)

ED (%)

Viscosity (cP)

x1

x2

x3

y1

ŷ1

y2

ŷ2

y3

1

-1

-1

0

48.9

46.8

51.4

51.5

3.03

2

1

-1

0

69.6

67.5

93.8

91.9

3.02

3

-1

1

0

49.7

51.8

51.1

53.0

3.04

4

1

1

0

72.2

74.3

74.7

74.6

3.06

5

-1

0

-1

51.8

51.8

57.1

55.6

3.03

6

1

0

-1

69.6

69.6

84.8

85.4

3.02

7

-1

0

1

56.4

56.4

58.6

58.0

3.02

8

1

0

1

81.7

81.7

88.6

90.1

3.03

9

0

-1

-1

46.5

48.7

62.3

63.7

3.04

10

0

1

-1

60.9

58.8

60.8

60.3

3.04

11

0

-1

1

59.1

61.2

71.3

71.8

3.04

12

0

1

1

65.0

62.9

60.8

59.4

3.03

13

0

0

0

69.9

69.2

72.5

72.6

3.06

14

0

0

0

69.5

69.2

69.1

72.6

3.05

15 0 0 0 69.3 69.2 76.2 72.6 3.04 Standard conditions: all experiments were performed using the same raw materials; at a scale 15.00 g (0.074 mol) of sebacic acid (purity >99,0); rate of stirring 200 rpm, in argon atmosphere. b All ŷ have been calculated from quadratic model. i a


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Esterification degree of poly(glycerol sebacate), ŷ1 (%). ŷ1 = 69.3 + 10.8 x1 + 2.96 x2 + 4.18 x3 +1.89 x1x3 – 2.10 x2x3 – 8.08 x22 – 3.27 x32 The diagram of the influence of esterification degree of poly(glycerol sebacate), ŷ1 on the reaction temperature x1 and reaction time x3, at the optimal molar ratio glycerine/sebacic acid, x2= –1 is shown in Figure 5.

Figure 5. Dependence of esterification degree of poly(glycerol sebacate), ŷ1, on the reaction, temperature, x2, and the reaction time, x3; x2 = –1. Conversion of carboxylic group, ŷ2, (%). ŷ2 = 72.6 + 15.5 x1 – 3.94 x2 – 6.63 x22 The diagram of the influence of conversion of carboxylic group, ŷ2 on the reaction temperature, x1 and the molar ratio glycerine/sebacic acid, x2 is shown in Figure 6.


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Figure 6. Dependence of conversion of carboxylic group SA, ŷ2, on the temperature, x1 and the molar ratio glycerine/sebacic acid, x2. Based on the obtained equations, which described the experimental data very well, an optimal point was calculated using the MS Solver tool.95 The criterion of optimization was to obtain the maximum value of monomers carboxylic group (ŷ2) with degree of PGS esterification (ŷ1) > 80%. The coordinates of the optimal point are the following: z1 = 150 °C, z2 = 2, z3 = 4 h. The result of the reaction under these conditions should be a degree of esterification of polymer with 88.8% and a conversion of COOH group of 88.1%. After the experiment, the PGS degree of esterification with 81.7% and 88.6% conversion of monomers (Table 4) was obtained. This confirms that the obtained equations describe well the investigated process.


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Table 4. Obtained and calculated results polycondensation of sebacic acid with glycerine in optimal conditions

Results

ED (%)

Conversion of COOH (%)

calculated

82.8

88.1

experimental

81.7

88.6

Purification of polycondensation product. The method to purify PGS prepolymer off unreacted sebacic acid and glycerine (Scheme 2) was developed. The post-reaction mixture was dissolved in dioxane for 24 hours in order to completely dissolve the polymer. Then the solution was poured into cold water and filtered. The sediment was dried under reduced pressure at 45 °C for 24 h. In the IR spectra (Supporting information Figure S1) the 1647 cm-1 band disappeared and the signal width decreased by 3390 cm-1, which provides evidence on a reduction in the number of OH groups. The signals in the spectrum are less widened and sharper. Upon the purification of PGS prepolymer, the acid and ester numbers were re-assessed and the level of esterification - calculated (Table 5). It was found that the EN made no change and therefore the number of ester bonds in the polymer did not change (it did not get hydrolysed during purification). The acid number decreased, which indicates the removal of unreacted sebacic acid. The level of esterification increased from 86% to 96.3%.

Scheme 2. Block Diagram of the purification of prepolymer poly (glycerol sebacate) at the Laboratory Scale


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Table 5. Obtained results of purification of poly (glycerol sebacate) PGS

AN

EN

ED

after reaction

59.5

365

86.0%

after purification

14.3

372

96.3%

Due to the solubility of dioxane in water, it is completely removed from the polymer during precipitation. Gas chromatography with heat space of the product after purification showed no remaining dioxane in the polymer (supplementary information, Figure S2). Therefore, the product can be used in medicine or pharmacy.

CONCLUSIONS We have developed an original method for rapid polycondensation of glycerine with sebacic acid. We have developed a technologically easy method for separating PGS using a solvent – dioxane – and cold water precipitation. The adequate models of monomers conversion and esterification degree of PGS were obtained. Optimal conditions for polycondensation with glycerine and sebacic acid were developed, in which PGS was obtained with a high conversion of carboxylic group ~89% and high esterification degree ~82%, containing no catalysts residues. ASSOCIATED CONTENT Supporting information The procedure of prepolymer poly (glycerol sebacate) analysis like an acid and aster number, esterification degree and conversion of COOH group in sebacic acid; IR spectra of poly (glycerol sebacate): after reaction, after purification (Figure S1); significance of coefficients of the


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regression equation for the esterification degree (Table S1) and the conversion of COOH groups (Table S2).

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Agnieszka Gadomska-Gajadhur 0000-0001-7686-1745 Paweł Ruśkowski 0000-0002-4589-0727 Notes The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS Financial support obtained from Warsaw University of Technology, Faculty of Chemistry, is gratefully acknowledged. This scientific research was financed from the budgetary funds on science projected for 2018-2022 as a research project under the "Diamond Grant" programme (DI 2017 000347 (ID 395680)). REFERENCES

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