Thebiodegradabilityofpolyesterblends Y. Cha and C.G. Pitt Research Triangle Institute, Research Triangle Park NC 27709, USA (Received 10 July 1989; revised 14 September 1989; accepted 19 September

1989)

Blends of poly(s-caprolactone) (PCL) and poly(L-lactic acid) (PM) with polyglycolic acid-co-l-lactic acid (PGLA) were prepared by three methods: compression moulding, coprecipitation, and solvent evaporation of a methylene chloride-in-water emulsion of the polymers. The rates of hydrolytic chain scission of each component of the blends were determined by deconvolution of GPC traces of samples maintained in phosphate buffer, pH 7.4,37%, for up to 3000 h. The observed rates were dependent on the method of blending. For compression moulded blends, the rate of chain scission of PGLA was decreased and that of PC1 and PLlA increased. A corresponding delay in the onset of weight loss was also observed. There was no evidence of blend miscibility. Keywords: Biodegradation, poly(e-caprolactone), poly(L-lactic acid), polyglycolic acid-co-L-lactic acid. polymer blends. hydrolysis, gel permeation chromatography

Aliphatic polyesters derived from glycolic acid, DL- and L-lactic acid, and c-caprolactone have found frequent application as biodegradable matrices for prosthetics’ and controlled drug delivery’. 3. The optimization of the key properties of these biomaterials, i.e. the permeability, the rate of biodegradation, and the tensile properties, has generally been achieved by copolymerization4-6. Blending of the homo- and copolymers represents an alternative but less exploited means of tailoring the material properties. The changes in the permeability of polyesters effected by blending are predictable and have already been used to tailor the rate and duration of drug delivery systems. For example, blending poly(s-caprolactone) (PCL) or its copolymers with increasing amounts of poly(L-lactic acid) (PLLA)‘, celluloses*,’ or other glassy polymers permits a systematic reduction in the permeability of the polymer matrix. In contrast to these diffusion studies, the biodegradation of blends is largely unexplored. Several recent publications7. lo suggest that blending may be used to manipulate the rates of biodegradation-controlled delivery of drugs, but the mechanism of the process is not known. We report here the effect of blending on the rates of hydrolytic degradation of the above polyesters and show that, despite the incompatibility of the blends, the rate of hydrolytic chain scission of each component is significantly modified by the presence of the second polymer.

METHODS PCL, PLLA and polyglycolic acid-co-L-lactic acid (PGLA) were prepared by bulk polymerization of redistilled c-caprolactone or recrystallized L-dilactide and diglycolide at Correspondence to Dr C.G. Pitt. The authors are presently at Amgen Inc.. Thousand Oaks, CA 9 1320. USA

140°C for 18 h in an evacuated glass vessel in the presence of stannous octoate4, 5. The polymers were purified by precipitation from methylene chloride with methanol and dried in vacua. The sample of PGLA was determined to contain 83 mol% of lactide by ’ H-n.m.r. spectroscopy (CDCI, solvent) using a Bruker Model Wm-250 Supercon spectrometer. Blends were prepared by casting common solutions of the polymers in methylene chloride, then compression moulding the cast films to a thickness of 0.6 mm in a Carver press for 2 min at 2000 p.s.i. then 1.5 min at 20 000 p.s.i. at elevated temperatures: PGLA 1 OO”C, PGLA-PCL and PCL 125-l 3O”C, PGLA-PLLA 190-200°C. Discs, diameter 0.64 cm, approx. 20 mg, were punched from the moulded films. Precipitated blends of PCL and PGLA were prepared by dissolution of a 1 g mixture of the two polymers in methylene chloride (6 ml), concentration of the continuously mixed solutionin vacua at 35”C, and addition of an excess of methanol. The precipitated mass was dried in vacua, and cut into 3 mm3 pieces (about 20 mg). Microspheres were prepared by the solvent evaporation method” at ambient pressures. Typically, a solution of the polyesters (300 mg) in CH,CI, (4 ml) was poured rapidly into 20 ml of water containing 0.4 wt%of poly(vinyl alcohol) (/VI, 25 000; 88% hydrolysed). The mixture was stirred with a magnetic stirrer to form an emulsion; stirring was continued at 37°C until the CH,CI, had evaporated. The microspheres were separated, washed with deionized water, and dried in vacua. Polymer hydrolysis was measured by immersing samples in 40 ml of 0.1 M phosphate buffer at pH 7.4 and 37°C. Duplicate samples were withdrawn at different time intervals and weight loss was determined gravimetrically after drying for 24 h in vacua. Molecular weights were determined by gel permeation chromatography (GPC) in chloroform using a set of five p-Styragel columns (Waters Assoc.) with nominal pore sizes of 1 05, 1 04, 1 03, 1 02, and o 1990 Butterworth

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1990, Vol 11 March

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Biodegradability of polymer blends: K Cha and C.G. Pitt

600

5 X 10’ nm, and an eluent flow rate of 1 ml/min. The GPC traces were evaluated by the universal calibration method’” using polystyrene standards (Waters Assoc., Ventron) and published Mark-Houwink constants for PGLA13, PCL14, and PLLA15. Curve fitting of the GPC traces of blends to two overlapping Gaussian functions was carried out using a least-squares computer program (RS?) on an IBM PC. Polymer crystallinity, or absence thereof, was determined by differential scanning calorimetry using a Perkin-Elmer Model DSC-2 instrument, a heating rate of 10 or 20”C/min, and an indium standard. The percentage crystallinity was derived from the measured heat of fusion using the reported heat of fusion of 139.5 J/g of 100% crystalline PCL”. Thermomechanical analysis (TMA) was carried out using a Perkin-Elmer Model DSC-2 instrument and a heating rate of 5”C/min. Dynamic mechanical analysis of blends was conducted with a Rheovibron and a temperature range of - 120 to 100°C.

-7

500

400

100

-

0

-

RESULTS AND DtSCUSSlON The rates of hydrolytic chain scission of blends of PCL with PGLA and PLLA with PGLA were first measured by immersion of compression moulded films in phosphate buffer at pH 7.4 and 37°C. At various time intervals, samples were retrieved and the changes in the molecular weights of the component polymers determined by GPC. Overlapping GPC peaks were deconvoluted analytically by the least-squares fit of two Gaussian curves to the data, after verifying that the unblended polymers peaks could be described by this function. Deconvolution using other functions, such as the Tung equation’? and the Wesslau or log-normal distribution’*, was less successful. An example of deconvoluted GPC peaks is shown in Figure 1. The results of the GPC measurements of PGLA-PCL and PGLA-PLLA blends are shown as semilog plots of /M, versus time in Figures 2 and 3. It has previously been established that the in v&-o degradation of PCL, PLLA, PGLA, and other polyesters occurs at the same rate in vitro, with no significant enzymatic contribution to the process4. Rather, biodegradation of these polyesters proceeds by random hydrolytic chain scission of ester links, until the molecular weight has decreased to the point that continued cleavage produces fragments small enough to diffuse from the polymer bulk; weight loss then ensues. The kinetic laws governing chain cleavage are derived from the assumption that cleavage is autocalysed by the carboxy end groups generated and is also proportional to the water and ester concentrations (Equation 7). While the number of cleavages is small, [HzO] and [Ester] may be considered constant and integration of Equation 7, coupled with the relationship [COOH] = M,-‘, leads to Equation 2. [COOW], = k’[COOHJO[H20][Ester]

(1)

M,’ = M,’ expf -kt)

(2)

Thus, a semilog plot of M, versus time is linear during this initial phase of degradation. It is evident from the semilog plots in Figures 2 and 3 that the linear relationship between ln(n/l,) and time is also observed with the compression moulded polyester blends, although curvature is observed at later times as degradation progresses. The rate constants (k) of Equation 2 estimated from the initial slopes of semilog plots of the experimental data in Figures 2 and 3 are listed in Tab/e 1. The effect of blending is to slow the rate of chain scission of the more

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2j

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ELUTION VOLUME

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100 -

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-100

-- Ib 27

1111111111111111111111 29 31 33 35 37 39

41

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ELUTiON VOLUME (ML) Figure 1 Gel permeation chromatography traces (outersolidlines] from [a) PCL and (bj a I:2 PCL-PGLA blend, and the least squares fit of Gaussian functions (a, + symbols) to the experimental data.

rapidly degraded polymer and to increase the rate of cleavage of the less reactive polymer, in approximate proportion to the weight fraction of each component. For the 1: 1 blends of PGLA with either PLLA or PCL, the rates of cleavage of PCL and PLLA are increased and that of PGLA decreased. Increasing the proportion of one component of the blend produces a weighted change in the rate constants, evident from the results with I:2 and 1 :3 blends. The rates of cleavage of the two components of the 1: 1 blends of both PCL:PGLA and PLLA:PGLA are nearly identical. Not unexpectedly, the retardation of the rate of

Biodegradability of polymer blends: Y. Cha and C.G. Pitt

Table 2 Weight loss (%) of PGLA and its blends with PCL as a function of time in phosphate buffer, pH 7.4, 37°C Polymer

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I 1000

500

TIME

I 2500

I 2000

1500

(HRS)

Figure 2 The change in the molecular weights (M,) of unblended (0) PCL and PGLA and 13 (+). 12 (X), 1: 1 (m) compression moulded blends of the same polymers, in phosphate buffer, pH 7.4, 37°C.

.0

20’00

1000

30bo

40’00

TIME(HRS)

Figure 3 The change in the molecular weights (M,) of unblended and compression moulded It1 blends of PGLA and PLLA in phosphate buffer, pH 7.4, 37°C. The initial M, of the unblended sample of PLLA was slightly smaller than that used to prepare the blend. Symbols: unblended PLLA (U), PGLA:PCL blend (0). precipitation (0); and solvent evaporation of an emulsion (X).

hydrolytic chain cleavage of PGLA in PCL-PGLA blends was accompanied by an increase in the induction period before weight loss. The weight losses of 1: 1, I:2 and 1:3 blends during a period of 4000 h are listed in Table 2. The greater the proportion of PCL, the slower the onset and extent of Table 1 Rate constants (X 1O4 h-‘) derived from initial slopes (first 1000 h) of semilog plots of the molecular weights (M,) of polyesters and their blends versus time in phosphate buffer, pH 7.4, 37°C Blend ratio of polymers

1a 1:l 1:2 1:3 0:l

1

:o

1:l 0:l

110

Precipitated

Moulded

Solvent

evaporated

PCL

PGLA

PCL

PGLA

PCL

PGLA

1.7 3.8 6.2 11

4.4 8.2 8.8 31

2.1

-

1.4

-

2.5 2.7 -

4.9 3.3 24

1.7 2.1 -

7.0 6.4 9.7

PLLA

PGLA

2.8 5.0

9.5 31

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1990, Vol 11 March

PGLAa PCL:PGLA PCL:PGLA PCL:PGLA PCLb

(1:3) (1:2) (1:l)

alnitial

10 000;

M,

500h

lOOOh

1500h

2010h

3020h

4000h

4 0 0 0 0

9 0 0 0 0

41 0 0 0 0

53 0 0 0 0

69 28 4.5 4 0

17 0

blnitial

M, 76 000.

weight loss. Unblended PCL (n/r, 76 000) lost no weight in this time period, consistent with earlier observations’g. Dynamic mechanical analysis measurements were undertaken to assess the miscibility of the compression moulded blends. The Ts of PCL at -60°C in 1: 1 blends with PGLA and PLLAwas unchanged, indicating lack of miscibility. The closeness of the Tgof PGLA and the T,,, of PCL prevented observation of the Ts of PGLA in the blend; however the failure to observe a new averaged Ts in the vicinity of 0°C also suggests lack of miscibility. The heat of fusion of PCL, measured by DSC, was proportional to the weight fraction of PCL incorporated in the blend, demonstrating no change in the crystallinity of PCL on blending. The lack of miscibility of the blends was not unexpected, because of the large difference in solubility parameters of the constituent polymers calculated from Fedor’s constants”,” : PCL 20.8; PLLA 22.7; PGLA 25.4 J”’ cmm3”. This lack of miscibility would appear to rule out a mechanistic explanation whereby the hydrolysis rates were determined by the weighted concentrations of the carboxy end groups of PGLA and PCL (cf. Equation l), the more acidic PGLA carboxy end group being the more effective catalyst. Similarly an increase in the water content of the blend associated with the more hydrophilic PGLA cannot be invoked if separate polymer domains exist. However, despite the apparent lack of miscibility, the large perturbation of the rates of chain scission suggested that there must be a strong interaction of the polymers or a significant change in their morphology on blending. The importance of the morphology of the polymers was examined by comparing the rates of hydrolysis of PCL:PGLA blends prepared by two additional methods. These were: coprecipitation from a common solution with a non-solvent and solvent evaporation of an emulsion in water. The latter procedure is a common method of preparation of microspheres for drug delivery. The result of these changes in sample preparation was a reduction in the rate of hydrolysis of unblended PGLA (Figure 4). as well as a change in the behaviour of the blends (figures5 6).The initial rateof hydrolysis of PGLA microspheres was approximately onethird of the rate of compression moulded PGLA discs. However, the rate increased with time and after 1500 h was comparable to that of compression moulded PGLA. The rate of hydrolysis of precipitated PGLAwas intermediate in value. The hydrolysis of PCL was less affected by the method of preparation, and the changes in molecular weight were small. The rates of hydrolysis of PCL in coprecipitated 1 :2 and 1 :3 blends with PGLA were the same and significantly lower than those observed with compression moulded blends (Table 7). The rates of hydrolysis of PGLA in microsphere blends with PCL were similar to the rates of compression moulded blends and slightly greater than the rates of coprecipitated blends. No correlation between hydrolysis rates and the

Biodegradability of polymer blends. Y Cha and C-G. Pm

v_

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_~

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PCL

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0 Lu

PGLA 108

g

0

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Figure 4 The change in the molacolar weights (M,j of PGlA in phosphate buffer. pH 7.4,3 7°C Samples were prepared& compression moolding (Oj, compression moulding as a 3: 1 PGLAPCL blend (Oj, precipitation (0). and solvent evaporation of an emulsion IXJ.

figtire 6 The change in the molecular werghts (NI,j oioobleoded (0) PCL and PGL/L and lt2 (X) and 1:3 (0) blends of the same polymers, in phosphate buffer, pH 7.4, 37°C. Samples were prepared by solvent evaporation of a methylene chlorrde solution of the polymers emulsified rn aqueous po/y(vinyl akohol).

mechanical strength4. It is also evident that the method of fabrication and the resulting morphology of the polymers and their blends play a critical role in determining their relative rates of hydrolytic degradation.

ACKNOWLEDGEMENTS This work was supported in part by the National Institute on Drug Abuse, Grant No. DABB 5-ROI -DA-36 16-03.

REFERENCES

d2 0

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TIME(HRS) Figure 5 The change in the molecular weights (M,j of unblended (UJ PCL and PGLA. and 1.2 (ij and 13 (OJ blends of the same polymers, in phosphate buffer, pH 7.4, 37°C. Samples were prepared by coprecipitation from methylene chloride with methanol. 5

or AHfusion

Ta of samples was observed. The initial crystallinities of unblended PCL, calculated from the heat of fusion, were 49% (moulded), 43% (microspheres) and 50% (precipitated). The Tgs of PGLA determined from the softening point by TMA were (n = 2): 31.8 + 1.8”C (moulded), 36.3 i 22°C (precipitated), and 34.2 Ifr 7.8”C (mi~rospheres}. While the molecular basisforthe observed differences in hydrolysis rates is not clear, the practical value of these results is the identification of a new means by which the properties of the polyesters may betailored for drug delivery. For example, PCL is much more permeable than PGLA but degrades very slowly. Blending of PCL with PGLA provides a means of retaining the permeability and form stability of PCL while increasing the rate of degradation. This is less easily accomplished by copolymerization; random copolymers of &-caprolactone with glycolide or lactide have comparable permeabilities to PCL, and degrade rapidly, but have little

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Hoffman, AS., Medical appltcations of polymeric fibers, /. Appi. Polym. Sci.. Appl. Poiym. Symp. 1977, 33, 3 t 3-334 Pttt, C.G. and Schindler. A., Btodegradatton of polymers, tn Controlled Drug Delivery (Ed. SD. Bruck), CRC Press, USA, 1983, pp 53-80 Heller. J., Biodegradable polymers in controlled drug delivery, CNt. Rev. Ther. Drug Carrier Syst. 1984, 1 I 39-90 Pitt, C.G., Jeffcoat, R.A., Schindler, A. and Zweidinger, R.A., Sustained drug deltveiy systems. I. The permeabrlity of polyja-caprolactcne). polyfot-lacttc acid), and thetr copolymers, J. Biomed. Mater. Res. 1979,13,497-507 Pitt, C.G., Gratzl, M.M., Ktmmel, G.L., Surles, J. and Schlndler. A., Altphatlc polyesters. Il. The degradation of poly(oL-lacttde), poly(ecaprolactone), and thew copolymers in viva, Biomateenals 198 1I 2, 215-220 Reed, A.M. and Gilding, D.K.. Biodegradable polymers for use tn surgery: poly(glycolic)/poly(lactic actd) home- and copolymers. 2. ln wtro degradation, Polymer 198 1, 22. 494-498 Cha, Y. and Pitt, C.G., A one-week subdermai delivery system for i-methadone based on biodegradable mkxocapsules. J Controlled R&ease 1988. 7. 69-78 Chang, R.K., Prtce. J.C. and Whttworth, C.W., Control of drug release rates through the use of mtxtures of polycaprolactone and cellulose acetate butyrate polymers, Pharm. Technol. 1986. 10, 24-33 Chang, A.K., Price, J.C. and Whltworth, C.W., Control of drug release rate by use of mixtures of polycaprolactone and cellulose acetate butyrate polymers Drug Dev. Ind. Pharm. 1987, 13. 1 1 19-l 135 Hutchinson, F.G. and Fun. B.J.A., Brodegradable polymers for the sustatned release of peptides. Trans. 609th Biochem. Sac. Meetrng, Leeds, UK. 1985, 13. 520-524 Deasy, P.B., Microencapsulation and Related Drug Processes, M. Dekker, New York, NY, 1984 Grubistc, Z., Remmp. P. and Benoit. Ii., A unwefsal calibratton for gel permeation chromatography, J. Polym. Sci, Part ff 1967. 5. 753 Pitt. C.G. and Gu. Z.W., Modification of the rates of charn cleavage of

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poly(s-caprolactone) and related polyesters in the solid state, J. Contraffed Reiease 1987, 4, 283-292 Koteske, J.V. and Lundberg, RD., Lactone polymers. Ii. Hydrodynamic properties and unperturbed dimensions of poly-s-caprotactone, J. Polym. Sci.. Part A2 1969. 7, 897-907 Schindler, A., Hibionada, Y. and Pitt, C.G., Aliphatic polyesters. III. Molecular weight and molecular weight distribution in atcohol initiated polymerization of s-caprofactone, & Poiym. Sci, &hem. Ed. 198X,20,3 19-326 Crescenzi, V.. Manzini. G., Calzolari, G. and Borri, C., Thermodynamics of Fusionof poly-~-p~p~lacton~ and poly-c-caprolactone. Comparative analysis of the melting of polylactone and polyester chains, Etrr. Polym~ J. 1972. 8. 449-463

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Tung, L.H., Fractionation of polyethylene. J. Polym. Sci. 1956, 20. 495-506 We&au, l-f., Die molekuiarg~ichtsuerte~lung einiger niederdruckpofyathytene. Macromol. &hem. 1956.20. 1 1 l- 142 Pitt, C.G., Chasalow, F.I.. Hibionada, Y.M., Klimas, D.M. and Schindler, A. Aliphatic polyesters. I, The degradation of poly(scaprolactone) in v&o. ./. &pi. PO&?. Sci. 196 1~ 26, 3779-3787 Fedors, RF., Method for estimating both solubility parameters and molar valumes of liquids, Polym. Eng. Sci. 1974, 14, 147154 Van Krevelen, D.W., Proper&es of Polymers. Their Estimstion and Correlation w&h Cbemicaf S%nztwe, Elsevier Scientific Publishing Co., New York, 1976. Ch 7