synthesis of poly(1,4-dioxan-2-one-co-trimethylene carbonate) for application in drug delivery...

Synthesis of Poly(1,4-dioxan-2-one-co-trimethylenecarbonate) for Application in Drug Delivery Systems

HONG WANG,1 JIAN HUA DONG,1 KUN YUAN QIU,1 ZHONG WEI GU2

1 Department of Polymer Science and Engineering, College of Chemistry and Molecular Engineering, Peking University,Beijing 100871, China

2 National Research Institute for Family Planning, Beijing 100080, China

Received 26 August 1997; accepted 2 December 1997

ABSTRACT: Poly(1,4-dioxan-2-one-co-trimethylene carbonate), P(DON-co-TMC), co-polymers with different compositions were synthesized by copolymerizations of 1,4-dioxan-2-one (DON) and trimethylene carbonate (TMC) at 1207C in the presence ofSn(Oct)2 . Their structures and compositions were determined with FT-IR and 1H-NMRspectroscopies. The intrinsic viscosities of copolymers increased with the increase of theTMC fraction in feed. The DSC results of copolymers showed that the glass transitiontemperatures (Tgs) of copolymers are lower than those of homopolymers. Most copoly-mers are amorphous except for one with a high DON composition. The hydrophilicityof the copolymers is in proportion with the DON molar fraction in the copolymers. Itwas found that the Levonorgestrel (LNG) release rate is dependent of the compositionand flexibility of polymer chains. The fastest one is the copolymer with nearly a equiva-lent fraction of DON to TMC. Among copolymers with other compositions, a higherDON fraction would be favorable to the release of LNG. All measurements demonstratean almost constant release rate in the period of 1 month. q 1998 John Wiley & Sons, Inc.J Polym Sci A: Polym Chem 36: 1301–1307, 1998Keywords: 1,4-dioxan-2-one; trimethylene carbonate; stannous octoate; drug deliv-ery system

INTRODUCTION dation and decline of the release rate.6 Poly(lac-tide-co-glycolide) has been used in ophthalmicDDS.7 In a period of 4 weeks, the drug can beThe application of biodegradable polymers as ma-

trices for sustained drug delivery systems (DDS) released completely and the profile of drug releasecan be controlled by the composition of copoly-has attracted much attention in the last decade.1

The studies on DDS of homopolymers or copolymers. The ring-opening copolymerizations of 1,3-dioxan-2-one with 1-caprolactone,8,9 (R ) -b-buty-mers of lactic acid (LA), glycolic acid (GA), and

1-caprolactone (CL) have been the subject of pre- rolactone with (R ) -3-methyl-4-oxa-6-hexanol-ide,10 and 2,2-dimethyltrimethylene carbonatevious publications.2–5 It has been reported thatwith L,L-lactide11 have been carried out, and thecopolymerization is an effective way to providemechanisms have been studied. Copolymerizationmaterials with different degradation rates andcan provide copolymers with low crystallinity,processibilities. The copolymers of 1-caprolactonewith lower melting temperature,8–11 or in non-and D,L-lactide, P(CL-co-LA), have been used ascrystalline form. Thus the degradation rates ofmatrices in DDS, which have shown a fast degra-copolymers are faster than those for relevant ho-mopolymers. The incorporation of an ester groupCorrespondence to: K. Y. Qiuinto poly(trimethylene carbonate) lead to the in-

Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 36, 1301–1307 (1998)q 1998 John Wiley & Sons, Inc. CCC 0887-624X/98/081301-07 crease in degradation rate.8

1301

8g72 97145p/ 8G72$$145P 03-20-98 17:01:03 polca W: Poly Chem

1302 WANG ET AL.

Poly(1,4-dioxan-2-one) (PDON) is a biodegrad- polymerization. TMC was synthesized accordingto a modified literature procedure.18 To a 1000 mLable and biocompatible polymer. It can degrade

completely in the body in about 180 days.12 PDON one-necked, round-bottomed flask fitted with acondenser were added 105 mL (111.3 g, 1.46 mol)has better flexibility and tensile strength than

PLA.13 It has been used to make monofilament of 1,3-propandiol, 400 mL (389.6 g, 3.30 mol) ofdiethyl carbonate, and 20 g of K2CO3. The solutionsutures with good tenacity and knotting and can

be applied clinically instead of multifilament PLA. was kept in an oil bath at 1207C and stirred for 3 hwhile CH3CH2OH was distilled out. The residualThe homopolymer of trimethylene carbonate

(TMC) has been revealed to be compatible and mixture was filtered, and the filtrate was concen-trated, giving crude product. The crude productdegradable to nontoxic compounds in the body

with an extremely slow rate.8 TMC is mainly used was distilled under the reduced pressure of 1mmHg in the presence of CaH2 and a few dropsto copolymerize with LA14 for preparing sutures

with improved flexibility. Recently the copolymer- of Sn(Oct)2 . The distillate at 1207C was collected.It solidified to white crystals while dropping inization of DON, GA, and TMC was reported for

preparing sutures with improved properties.15,16 the collecting flask. This product is recrystallizedthree times in THF/ether mixed solvent (8 : 4,The investigation of the application of polymers

of DON and TMC in DDS, however, has rarely v/v). After being dried in a vacuum for 24 h, itwas kept drying in a desiccator, giving mp 45.5–been reported.

In this paper, the synthesis of copolymers of 46.57C (literature mp: 457C19). Yield: 36%. 1H-NMR (CDCl3, TMS, ppm): 4.47 (t, 4H), 2.16DON with TMC is presented. It was expected to

obtain a new kind of biodegradable polymer by (quint., 2H).copolymerization of DON with TMC. These copol-ymers have shown properties quite different from

General Procedure for Copolymerization ofthose of relevant homopolymers in morphology,DON and TMChydrophilicity, and flexibility. DDS based on those

copolymers show that the accumulative release Calculated amounts of TMC were charged into aflame-dried glass tube. The system was connectedamount of drug is nearly in linear proportion with

time for a 1 month period. This is much better with a vacuum line, then dried at 1107C for 30min, and purged with nitrogen. Under nitrogen,than DDS of P(CL-co-LA) or other copolymers

and the homopolymers of PDON and PTMC. the calculated amount of fresh DON and theproper amount of Sn(Oct)2 stock solution werecharged into the tube with a flame-dried syringe.The tube with monomers and Sn(Oct)2 mixtureEXPERIMENTALwas purged with nitrogen. After being sealed ina vacuum, it was heated and kept at 1207C for 10Materialsh. The copolymer was dissolved in CHCl3 and then

1,3-Propandiol (Beijing Chemical Factory), di- precipitated in methanol. The crude product wasethyl carbonate (J. T. Baker Chemicals B.V., GC dried under vacuum until constant weight (W0) .99%), and Sn(Oct)2 (Pfaltz & Bauer, Inc.) were It was further purified by immersing into THF,used as received. The stock solution of Sn(Oct)2 the solvent of PTMC, for 3 days in order to removein cyclohexane (0.3849 mol/L) was used as cata- the homopolymers of PTMC. The copolymer waslyst for the polymerization. Cyclohexane was dis- dried in vacuum at ambient temperature to con-tilled over sodium. Levonorgestrel (Beijing No. 3 stant weight (W1) .Pharmaceutical Factory) and the other solventsand reagents were domestic products and used as

Preparation of P(DON-co-TMC) Matrix Loadingreceived.Levonorgestrel and Release Experiment

Calculated P(DON-co-TMC) copolymers and Lev-Synthesis of 1,4-Dioxan-2-one (DON) and 1,3-onorgestrel (LNG) were dissolved in dichloro-Dioxan-2-one (Trimethylene Carbonate, TMC)methane, and then the solvent was evaporatedMonomersnaturally and dried under vacuum to constantweight. The copolymer and LNG mixtures were1,4-Dioxan-2-one (DON) was synthesized and

purified according to the procedure in our previ- pressed into circular cylinders under the pressureof 19.6 kPa. The cylinders were immersed in 15%ous paper17 and distilled over CaH2 just before


P(DON-CO-TMC) FOR DRUG DELIVERY 1303

ferential scanning calorimeter with a heatingrate of 107C/min. Wide-angle X-ray diffraction(WAXD) analyses were carried out on a Ragua X-ray refraction meter equipped with a Cu Ka1 (lÅ 0.1542 nm) source using the pieces pressed withP(DON-co-TMC) samples heated first and thencooled naturally. Dynamic contact angles (DCA)were obtained on a DCA-322 dynamic contactangle analyzer at 377C with film on a glass plate.Ultraviolet (UV) spectra were measured on thePUB700 Series UV/vis spectrophotometer.

Scheme 1. RESULTS AND DISCUSSION

Synthesis and Characterization of P-ethanol/water (v/v) solvent mixture. They were (DON-co-TMC)kept in a shaking bath with constant temperatureof 377C. The immersion solvent was refreshed reg- Copolymers P(DON-co-TMC) (PDT) were syn-

thesized by the copolymerization of DON withularly, and in the meantime the absorbency bandsof the samples at 248 nm on UV spectra were TMC using Sn(Oct)2 as catalyst. The copolymer-

ization reaction is illustrated in Scheme 1. Therecorded.copolymerizations with various mole fractions ofDON in feed, fDONs, from 80.7% to 19.2%, were

Characterizations carried out and the data for DON copolymeriza-tion with TMC are compiled in Table I. It can beThe 400 MHz 1H-NMR spectra were recorded on

a Bruker ARX400 spectrometer at room tempera- seen that the intrinsic viscosity ([h] ) of copoly-mers increased with the increase of fTMC . Theture. Tetramethylsilane (TMS) served as internal

reference for all 1H-NMR measurements, and yield is quite close to that for homopolymerizationof DON but lower than that of TMC.CDCl3 was used as solvent. Fourier transform in-

frared (FT-IR) spectra were measured using a Figure 1 shows the 1H-NMR spectrum of copol-ymers PDT2. The chemical shift d of c belongs toNicolet Magna-IR 750 spectrometer with KBr

pellets. Intrinsic viscosity of copolymers was the two protons of {O{CH2{CO{ in DONunits, and a and d belong to the four protons ofdetermined with a Ubbelohde viscometer at 30

{ 0.057C using tetrachloroethane as solvent. Dif- {O{CH2CH2{OCO{ in DON units. The d ofb is assigned to the four protons {O{CH2{ offerential scanning calorimetry (DSC) thermo-

grams were recorded on a Dupont DSC-1090 dif- the TMC units, and the d of e belongs to the two

Table I. Copolymerization of DON and TMC in the Presence of Sn(Oct)2a

Sample DON (g) TMC (g) fDONd W0 (g) W1

b (g) FDONe Yieldc (%) Tg (7C)f [h] (dL/g)

PDON 2.50 1 1.87 1 74.8 017g

PDT1 3.75 0.90 0.807 3.22 2.95 0.790 69.2 020.9 0.29PDT2 2.75 1.89 0.593 3.20 3.12 0.591 69.0 021.5 0.44PDT3 1.25 1.80 0.423 1.87 1.80 0.396 61.2 021.2 0.58PDT4 0.50 2.40 0.192 2.26 2.06 0.200 77.8 019.3 1.00PTMC 2.50 0 2.32 0 90.9 015.8 3.11

a ([DON] / [TMC])/[Sn(Oct)2] Å 2000, polymerizing at 1207C for 10 h.b Weight of copolymer after immersion in THF.c Calculated by W0/(WDON / WTMC) 1 100%.d DON mole fraction in feed.e DON mole fraction in copolymer determined by 1H-NMR spectra.f Obtained from DSC.g Literature data.8


1304 WANG ET AL.

Figure 3. Correlation between the intensity ratioFigure 1. 1H-NMR spectrum of P(DON-co-TMC) co- of absorbance at 1269 cm01 over that at 1141 cm01

polymer (PDT2). and DON mole fraction in copolymer determined by1H-NMR.

protons {OCH2CH2CH2OCO{ of the TMCunits. The absorbency bands at 1269 cm01 can beunits. The mole fraction of DON in the copolymer,assigned to the TMC units (the pure PTMC givesFDON , was determined from the integration ratioan absorbency at 1244 cm01) , and those at 1134of d of the PDON segment at d 3.81 ppm over thatand 1209 cm01 can be assigned to the DON units.of e of the PTMC segment at d 2.05 ppm. TheIt can be seen clearly that the intensity ratios ofresults determined from 1H-NMR are listed inthe two absorbencies mentioned above are in lin-Table I. It can be seen that FDON at the highestear proportion with FDON , as shown in Figure 3.conversion was nearly equal to the relevant fDON ,In other words, a new method for the determina-as illustrated in Figure 2. This fact indicated thattion of the composition of PDT has been estab-the compositions of the copolymers could be ad-lished.justed by varying the feed compositions.

In the FT-IR spectra of PDON, PTMC, and thecopolymer PDT, the absorption around 1747 cm01

Thermal Analysis of Copolymerscomprises overlapped characteristic absorbency

The DSC thermograms for the glass transitionbands of the carbonyl groups of DON and the TMCtemperature, Tg , of copolymers were recordedwith the samples cooled rapidly by immersing inliquid nitrogen immediately after being heated to1507C in order to obtain an amorphous sample,and the thermograms for melting point, Tm , wererecorded with the samples cooled naturally to am-bient temperature after being heated to 1207C.The experimental data are listed in Table I.

PDON is a semicrystallized polymer, whilePTMC is an amorphous polymer. As expected, themelting point of PDON, Tm , was measured as

Figure 2. DON mole fraction in copolymers at high-est conversion determined by 1H-NMR varying as afunction of DON molar fraction in feed. Figure 4. WAXD graph of PDT1.



mers depend on the copolymer composition, asshown in Figure 5. The Tgs of PDT were lowerthan that of either PDON or PTMC homopoly-mers, giving the lowest value when FDON is 60%.This can be explained as follows: The structures oftwo monomer units, DON and TMC, are different,and the chains composed of DON and TMC unitscannot pile up compactly like PDON or PTMCchains. The movement of the copolymer chainsis more facile than observed both homopolymers.This would be favorable to the diffusion of bothsolvents and drugs if the copolymers are used asmatrices in DDS.

Hydrophilicity of CopolymersFigure 5. Correlation between glass transition tem-perature, Tg , and TMC mole fraction in copolymer. It is well-known that drug delivery rate in DDS

is related to the permeating rate of H2O into thematrix. Higher hydrophilicity can accelerate the1107C, which is very close to the value in the liter-permeation of water and improve drug diffusionature. The literature values for PDON ([h] Å 0.59rate.dL/g) are as follows: Tg Å 0177C, Tm Å 1117C.13

The hydrophilicity can be well determined byThe glass transition temperature of PDONdynamic contact angles. The measuring resultscould not be detected in the present experi-are listed in Table II. It can be seen that the acced-ments. As expected, the Tm of PTMC could noting angle ua of PDON is lower than that of PTMC,be measured. PTMC cannot crystallize when itswhich indicated that the hydrophilicity of PDONmolecular weight exceeds 12,000. The copoly-is stronger than that of PTMC. Figure 6 showsmers PDT showed different thermal propertiesthat the acceding angle ua decreased sharply withwith both homopolymers. For example, the sam-the increase of DON fraction in the copolymers.ple PDT1 with high FDON gave a Tm value of

657C, which was much lower than that of PDON.This fact indicated that there were DON se- Release of LNG from the P(DON-co-TMC)quences long enough to crystallize in the copoly- Copolymer Matrixmer backbones. With the increase of TMC con-tent, the DON sequences in copolymers became The DDS compositions using copolymers as ma-

trices loading Levonorgestrel (LNG) are listed invery short and impossible to crystallize. It wasfurther proved by the results of WAXD measure- Table III.

The amount of LNG released per day wasment; as can be seen from Figure 4, only whenthe content of DON in the copolymer is high determined according to the absorbency of immer-

sion solution at 248 nm measured in a UV spec-enough, FDON ¢ 0.790, could two sharp diffrac-tion peaks at 21.48 and 23.407 be observed trometer.

From Figure 7 it can be observed that the burstwhich are attributed to crystallites of shortPDON segments in copolymer. effect of all samples was small, and the LNG re-

lease rate increased in the following order: PDT2The glass transition temperatures of copoly-

Table II. DCA Data for P(DON-co-TMC) Copolymers

No.a PDON PDT1 PDT2 PDT3 PDT4 PTMC

ua (deg) in cycle 1 51.44 51.72 66.22 69.05 80.42 83.94ua (deg) in cycle 2 42.93 49.07 55.70 58.42 72.23 89.03ur (deg) in cycle 1 24.37 33.82 32.11 26.36 28.44 30.55ur (deg) in cycle 2 22.08 34.21 24.99 23.84 28.21 27.25

a ua (deg): acceding angle. ur (deg): receding angle.


1306 WANG ET AL.

Figure 7. Release rate of LNG from PDT matrices.

Figure 6. DCA varying as a function of DON molefraction in copolymer, FDON .

DDS samples revealed the occurrence of degrada-tion of the copolymers.

Figure 8 shows that the graph of accumulativeú PDT3 ú PDT1 ú PDT4. It can be explained asrelease of LNG versus time gave nearly straightfollows. The chains of PDT1 and PDT4 piled uplines, indicating that the LNG release is zero or-more closely than those of PDT2 and PDT3 (cf.der. Thus, LNG can be released at nearly constantFig. 5) so that the solvent permeation in PDT1rate for 25 days.and PDT4 matrices is more difficult, which ob-

structed diffusion of LNG. In the matrices ofPDT2 and PDT3 (or PDT1 and PDT4) the matri-

CONCLUSIONSces with higher FDON have stronger hydrophilicityand thus result in higher water permeation and

DON and TMC can be copolymerized in the pres-LNG diffusion.ence of Sn(Oct)2 providing copolymers P(DON-All copolymers show much improved drug re-co-TMC) with different compositions. At highestlease behavior than homopolymers. PTMC showedconversion the copolymer compositions are nearlya faster release rate during the initial stage andthe same as the corresponding feed composition.then a decline in release rate, i.e. burst release. OnIn copolymers with higher DON fractions thethe other hand, the DDS based on PDON showedDON sequences could be partially crystallized.a lower release rate due to the slow diffusion ofThe hydrophilicity of P(DON-co-TMC) becomesLNG and water in crystalline PDON. The homoge-stronger as DON fractions increased. The releaseneity of the LNG dispersed was improved in copoly-of LNG from P(DON-co-TMC) matrices did notmers, and the release was mainly diffusion con-show a burst effect, and for a 25 day period thetrolled, especially in the initial stage.

As measured by 1H-NMR, the composition ofPDT kept constant after 25 days of the drug re-lease test while obvious degradation is observed.The weight loss, about 12% (wt) for 25 days, of

Table III. LNG Contents in DDS Using PDTCopolymer as Matrices

Sample FDON LNG (%) W (g) LNG (mg)

PDON 1.000 19.48 0.0188 3.662PDT1 0.790 20.17 0.0218 4.397PDT2 0.591 20.28 0.0229 4.644PDT3 0.396 19.94 0.0228 4.546PDT4 0.200 20.17 0.0230 4.639

Figure 8. Correlation between cumulative release ofPTMC 0.000 19.81 0.0129 2.555LNG from PDT matrices and time.



7. S. H. Hyon, Polymer Prepr. (Am. Chem. Soc. Polym.release rate is almost constant. The copolymersDiv.) , 37 (2), 125 (1996).with a nearly equivalent molar ratio of DON to

8. A.-C. Albertsson and M. Eklund, J. Polym. Sci.,TMC units show the fastest release rate of LNG.Polym. Chem., 32, 265 (1994).

9. A.-C. Albertsson and M. Eklund, J. Appl. Polym.The authors are grateful to the National Natural Sci., 57, 87 (1995).Science Foundation of China (Project 29234093) for 10. Y. Hori and A. Yamaguchi, Macromolecules, 28,financial support of this work. 406 (1995).

11. P. Schmidt, H. Keul, and H. Hocker, Macromole-cules, 29, 3674 (1996).

12. H. L. Lin, C. C. Chu, and D. Grubb, J. Biomed.REFERENCES AND NOTESMater. Res., 27, 153 (1993).

13. N. Doddi and C. C. Versfelt, U.S. Pat. 40529881. T. Hayashi, Prog. Polym. Sci., 19, 663 (1994). (1976-01-12).2. B. Buchholz, J. Polym. Sci., Part A: Polym. Chem., 14. B. Buchholz, J. Mater. Sci., Mater. Med., 4, 381

32 (11), 2099 (1994). (1993).3. J. W. Leenslag and A. J. Pennings, Makromol. 15. M. S. Roby, C.-K. Liu, and S. L. Bennett, Eur. Pat.

Chem., 188, 1809 (1987). 626,404 (1994-11-30).4. Y. X. Li and X. D. Feng, Makromol. Chem. Mac- 16. C. K. Liu and R. P. Stevenson, Eur. Pat. EP654,549

romol. Symp., 33, 253 (1990). (1995-5-24).5. X. D. Feng, C. X. Song, and W. Y. Chen, J. Polym. 17. H. Wang, J. H. Dong, K. Y. Qiu, and Z. W. Gu,

Sci., Polym. Lett. Ed., 21 (8), 593 (1983). Polym. Sin. Acta, 3, 329 (1997).6. C. G. Pitt, D. Christensen, R. Jeffcoat, G. L. Kim- 18. Z. Y. Zhu, A. G. Einset, C.-Y. Yang, W.-X. Chen,

mel, A. Schindler, M. E. Wall, and R. A. Zweidinger, and G. E. Wnek, Macromolecules, 27 (15), 4076Proceedings: Drug Delivery Systems, by L. H. Ga- (1994).belnik, Ed., DHEW Publication No. (NIH), 77:1238, 19. T. Ariga, T. Takata, and T. Endo, J. Polym. Sci.,

Part A: Polym. Chem., 31, 581 (1993).Baltimore, MD, 1977, p. 142.


synthesis of poly(1,4-dioxan-2-one-co-trimethylene carbonate) for application in drug delivery...

Documents