Kinetics of curing and physicomechanical behavior of silicone membrane

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Joumal of Controlled Release, 14 (1990) 11-19 Elsevier Science Publishers B.V., Amsterdam

KINETICS OF CURING AND PHYSICOMECHANICAL MEMBRANE

BEHAVIOR OF SILICONE

Robin H. Bogner’. Jue-Chen Liu2 and Yie W. Chien* Controlled Drug-Delivery Research Center, Rutgers, The State University of New Jersey, College of Pharmacy, P. 0. Box 789, Busch Campus, Pisca ta way, /Vew Jersey 08855-0789 (Received July 17, 1989; accepted November

Keywords: silicone membrane;

curing kinetics;

(U.S. A .,J

30, ‘I 989) crosslinking;

controlled

release membrane

The curing kinetics and cure dependence of properties of a silicone membrane were evaluated. The curing process has been shown to be quite temperature sensitive, suggesting that a longer processing time is required to cure the device at a more moderate temperature. However, curing temperature results at room in a substant~lly ~oser~lymer ~twork in the membrane. In order to invest~ate the cure depe~ence of membra~ pro~rties~ stable ~rt~lly cured membra~s were prepared. The elasticity of partially cured membranes was observed to drop dramatically. However, the membrane permeability to testosterone for even the most poorly cured membranes was noted to be within the normal variation in permeability of fully cured membranes.

INTRODUCTIDN Since 1968, when silicone was shown as a potential controlled release barrier for many steroid drugs [ 11, silicone polymer has been investigated and used to control the release of drugs from many types of dosage forms including transdermal patches [ 21, vaginal devices [ 3,4 1, intra-uterine devices [ 41, and oral tablets [ 51. As with most polymers, these silicone-based controlled release devices may be fabricated by extruding, molding, calendering, casting or spraying techniques. Since the silicone elastomer used in these devices is a thermosetting polymer, it must also be cured in order to main‘AFPE Fellow. Current Address: University of Connecticut, School of Pharmacy, Storrs, CT 06268, U.S.A. ‘Current address: Technology Resource Center, Johnson & Johnson Baby Products, Co., Skillman, NJ 08558, U.S.A. *To whom correspondence about this paper should be addressed.

0168-3659/90/$03.50

0 1990 -

tain its shape. The curing process consists of forming covalent crosslinks between polymer chains to form a single large network structure. Chemically, silicone is typically cured or crosslinked by addition, condensation or free radical reaction [ 6 1. In fabricating dosage forms, all processes that can add variability to the end product must be investigated, validated and controlled. In the case of silicone devices, the fabrication includes the curing process which may be a source of variability in the handling and drug release properties of the device. It is this potential variability that is explored in the present report. The literature is somewhat uncertain in reporting the effect of crosslinking or curing on the permeability of drug molecules through silicone thermosets. Robb [ 7 J reported that there is relatively little effect of crosslinking density on silicone rubber permeability to gases. Indeed, there were greater changes in the me-

Elsevier Science Publishers B.V.

12

chanical properties than the permeability of the silicone rubber with greater curing. However, one should bear in mind that drug penetrants are much larger molecules than gases. Other investigators [8] have shown that levonorgestrel release from poly (vinyl methylsiloxane ) decreases with increasing radiation crosslinking. Chien and Lau [9] also observed that both in vitro and in uiuo release of a synthetic progestin from a hydrophilic poly (methacrylate) polymer decreases with increasing extent of crosslinking. The results were attributed to the decrease in porosity and increase in tortuosity. The purpose of the present work was to follow the kinetics of the curing process of a commercially available silicone polymer, as well as to evaluate its elasticity and permeability as a function of curing.

MATERIALS

AND METHODS

Polymer

Silastic medical grade ETR Elastomer Q74735 (Lot # HH127030), a thermosetting silicone polymer consisting of components A and B, was donated by the manufacturer (Dow Corning, Midland, MI). From this research and literature sources, it appears that the silicone polymer consists of a dimethylsiloxane polymer with some vinyl methylsiloxane and hydrogenmethylsiloxane units for crosslinking, reinforcing silica (which has been removed in our processing), a platinum catalyst, and a volatile inhibitor to retard the addition reaction during storage and processing. Once the inhib-

itor is driven off by heating, the curing reaction is catalyzed (Fig. 1) . Membrane

Dispersions of 10% component A and 10% component B were prepared separately in a solvent system consisting of 45% (w/w) isopentane in methylene chloride [lo]. Complete dispersion was assured by mixing for 15 hours at 15°C in a sealed, jacketed beaker with a magnetic stirrer (Bellco Glass, Vineland, NJ). For the curing kinetics studies, equal amounts of each dispersion were combined and mixed for 1 hour. However, to prepare stable partially cured membranes, varying amounts of each dispersion were combined and mixed for 1 hour. In both cases, the mixed dispersions were allowed to stand for one hour to allow silica aggregates to settle out. The polymer solution was then withdrawn from the top of the dispersion and cast in Teflon petrie dishes. Great care was exercised in order to avoid including the settled filler aggregates in the cast membranes. The membranes were then maintained at 0’ C for 2 hours to allow the solvent to evaporate completely. The resulting membranes each weighed approximately 1.2 g. Curing Oven curing

The curing kinetics at low to moderate temperatures was studies using a laboratory oven. Uncured membranes in their Teflon dishes were either placed in a laboratory oven at 37,50, 70 and 90°C or in a dark ambient environment (25°C) for curing. At predetermined time intervals, membranes were removed and the curing reaction was quenched at 0 oC. These membranes were evaluated by swelling (see below ) . Differential

Fig. 1. Silicone curing involving addition reaction.

preparation

scanning

calorimetry

At higher temperatures, the curing process was followed in a differential scanning calorimeter (DSC) operated in the isothermal mode.

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Uncured membranes were maintained at 0°C and their DSC studies were conducted within 3 hours of preparation. Samples (50 2 1 mg) of the uncured silicone membranes were weighed to the nearest microgram into aluminum DSC pans and analyzed straightaway. The DSC chamber (Perkin-Elmer, DSC-7, Norwald, CT) was continuously flushed with nitrogen throughout the experiment. The heat sink was maintained at - 60’ C with refrigeration. The samples were loaded into the DSC sample chamber at O”C, allowed to thermally equilibrate (l-3 min ) and raised to the isothermal curing temperature over 60 seconds. Once the isothermal temperature was reached, the heat flow from the silicone samples was monitored to completion of the reaction. For each isothermal temperature (85,90,95 and 100 oC ) studied, five samples were analyzed.

Membrane

evaluation

Permeability

Permeation rates of testosterone through the test membranes were measured using the Ghannam-Chien permeation system [ 111. The average membrane thickness was determined by measuring the thickness at 5 points on each membrane. The donor medium was 170 ml of 45% (w/w) aqueous poly (ethylene glycol) (MW 400) presaturated with testosterone and maintained at saturation. The receptor medium was 170 ml of 45% (w/w) aqueous poly (ethylene glycol) (MW 400). Both media were maintained at 37’ C prior to use. The stirring rate was set at 425 rpm. Samples of 10 ml were withdrawn from the receptor medium and replaced with fresh medium at regular intervals. Samples were analyzed spectrophotometrically (Perkin Elmer 590A, Norwalk, CT) at 245 nm. The permeation rates were determined from the linear flux and normalized for the cross-sectional area and thickness of the membrane. Permeation experiments were run in triplicate.

Swelling

Membranes were removed from their Teflon dishes, weighed, and immersed in 100 ml of casting solvent which was maintained at 15’ C. Swelling of the membranes was monitored gravimetrically until equilibrium was reached. Experiments were run in triplicate.

Mechanical testing A 2 cm-wide sample was cut from each cured

membrane. The average thickness of the sample was determined. The membrane sample was then mounted in the clamps of a tensile tester (John Chatillon & Sons, NY) with a 3 cmlength of membrane exposed. The membrane was elongated at a constant rate of 15.2 mm/ min, while the reactive force of the membrane was measured. The elasticity of each membrane was determined by the retractive force/ elongation/cross-sectional area of the membrane. Triplicate samples were tested.

DATA ANALYSIS

The extent of cure was measured in two ways: (1) from the degree of crosslinking as determined from membrane swelling and (2) from the fraction of heat released during the curing reaction. The raw data from the swelling experiments consists of an initial weight of the membrane, three values for its swollen weight and a final dried weight. The degree of swelling of each membrane can be defined by: % (w/w)

swollen =

swollen wt. -final final wt.

wt.

x100

(1)

and since the weight of the swollen membrane minus the final dried weight is equal to the weight of the solvent imbided into the polymer network, then the volume degree of swelling can

14

be derived from eqn. (1). For the present case this is:

x*=0.39+0.45x

v, x

(6, - 7.70)2 RT

% (v/v) swollen = % (w/w)

sollen x &

(2)

where the factor U/O.884 is the ratio of polymer density to solvent density. Equation (2) assumes that the density of the solvent in the swollen membrane is not different from its neat density. Equation (2) also assumes that neither component of the solvent system is preferentially sorbed into the polymer network. In thermodynamic treatments of polymer swelling, the degree of swelling is defined by 02m, the volume fraction of polymer in the swollen film at maximum swelling. Equation (3 ) converts the previously defined parameter, % (v/ v) swollen, to u2m. 100 02, = % (v/v) swollen + 100

(3)

Flory and Rehner [12] derived an equation relating the degree of swelling, uzm,to the effective number of crosslinks in the polymer network, ye. This derivation assumes that the crosslinks are tetrafunctional and randomly distributed throughout the network. The resulting equation can be rearranged to yield the crosslinking density, v,/ V,. V.2 -=VO

Pdl-~2m) +02,+xl&J VlX(V ;Lz- &J2)

(4)

where V, is the volume of the unswollen polymer network, V, is the molar volume of the solvent and x1 is the solvent/polymer interaction parameter. The parameter V, is calculated by taking the volume average of the molar volume of each component in the solvent (assuming the molar volume of each component in the mixed solvent is not different from its neat phase value). The interaction parameter, x1, can be calculated from the solubility parameters of the solvent and polymer using the equation of Bueche [ 131 for poly (dimethylsiloxane):

where 6, is the solubility parameter of the solvent, 7.70 is the solubility parameter of poly (dimethylsiloxane), R is the gas constant, T is the absolute temperature, and 0.39 and 0.45 are empirical values. For the present system the value of x1 is 0.39. By substituting this value for x1 and the calculated value for VI into eqn. (4), the value of the crosslinking density for each film can be directly determined. From the crosslinking density, v,/V,,, an equation can be derived to determine the number of siloxane units between crosslinks, IV,_,.

(6) for a lightly crosslinked network. Both the crosslinking density and the number of siloxane units between crosslinks are measures of the extent of cure. From the isothermal profile obtained from DSC, the extent of reaction, & at each time interval was calculated using eqn. (7). t dq 5= jdldt,r* dt dt t’ L’

(7)

where dq/dt is the differential heat flow from the sample and t’ marks the beginning of the curing exotherm. This analysis assumes that the extent of reaction is proportional to the measured heat of reaction. The extent of reaction was plotted as a function of time to obtain the curing profile for each curing temperature.

RESULTS AND DISCUSSION Curing kinetics

The curing kinetics of the silicone elastomer was determined by either oven curing or DSC

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curing. For the oven-cured membranes, the degree of cure at different time intervals was determined by analyzing swelling data to obtain the crosslinking density of the membrane. The results of this analysis are shown in Fig. 2. The curing takes place within 14 minutes at 90°C but this temperature may be too high for the processing of some drugs. In cases where processing time is not so critical, the silicone can be adequately cured at lower temperatures which are more suitable for most drugs. However, the crosslinking density of a membrane cured at room temperature is only 75% of the value for membranes cured at elevated temperatures. So, curing temperatures below 37°C should be used with caution. The lower degree of cure at 25 “C may be caused by a poisoning of the curing reaction by some trace atmospheric gas. This possibility could occur in the present studies since, it has been reported that the crosslinking reaction can be inhibited by amines, sulfur, nitrogen, oxide and carbon monoxide [ 141. In order to get a more detailed look at the

kinetic profiles of the curing reaction, uncured samples were analyzed by isothermal DSC. A typical DSC profile is shown in Fig. 3. Generally, these profiles show a 80-100 mW endotherm followed by a 2-5 mW exotherm. The endotherm is due to a thermal lag of the sample during heating to the isothermal temperature, while the exotherm is the result of heat produced by the curing reaction. Several methods of reducing the endotherm were explored. One method involved subtracting the thermal profile of the cured sample from the corresponding uncured sample with poor results. Instead, the heating rate from the load temperature to the curing temperature was optimized. This optimum heating rate reduced the equilibration endotherm, while capturing the maximum exotherm, and was used in all the experiments reported here. The apparent heat of reaction of curing was determined to be -41.8 kJ/mol of crosslinks formed. Assuming that all of the heat produced is accounted for, the extent of cure can be determined by the partial area under the curve in Fig. 3 by using eqn. (7). The results of 6 5

.---------------

Temp.EO’C

4 3 2 1

0

12

3

4

5

6

7’0

4

Time (day)

6

12

16

20

0 0

40

60

Time (how)

120

160

Time (min)

-5

0

10

20

30 lime

(tin)

40

50

60

‘0

-

Temp.9U’C

10

20 The

30

(min)

Fig. 2. Curing profiles (crosslinking densities vs. time) for silicone membranes cured in a laboratory oven at five different temperatures.

16

3 E

31.5

Fig. 3. Heat flow profile for the curing of silicone elastomer (DSC).

x0

r

ETR Q7-4735 at 100°C in a differential

TABLE 1 Kinetic parameters

OL 0

scanning

1

2

3

4

5

-6

obtained from oven curing

T (“C)

k0 (%/min)

t,,, (mm)

25 37 50 70 90

0.027 0.29 2.0 4.5 6.0

350 210 51 8.1 4.2

Time (min)

Fig. 4. DSC during profiles for silicone elastomer at various temperatures.

this analysis yield the profiles in Fig. 4. The profiles obtained from the DSC analysis strongly suggest a zero-order reaction with a time lag, particularly in the range of 0.2 < << 0.9. While this mathematical analysis is not meant to be a theoretical treatment of the data, it does yield some parameters that are useful for comparison. Tables 1 and 2 summarize the kinetic parameters for ovenand DSC-curing, respectively. A noticeable contrast between the data in the

TABLE 2 Kinetic parameters

obtained from DSC curing

T

k,

4,

(“C)

(%/min)

(min)

85 90 95 100

32.1 73.3 102.7 131.5

1.2 1.0 0.7 0.6

calorimeter

17

two tables is that curing occurs more rapidly in the DSC chamber than in the oven. The DSC curing process is presumably less complicated by heat transfer considerations by the very design of the equipment. This could account for the differences in the two sets of results. There were differences, however, not only in the curing environments, but also in the methods used for data collection and analysis. This may also account for some of the differences between the two sets of data. While there are differences in the absolute values of kinetic parameters (rate constant kO, 7’) in Talagtime tlag, and curing temperature bles 1 and 2, it is clear from the results in both tables that the curing rate is quite temperature dependent. The curing rate increases with increasing curing temperature. Thus, curing conditions must be carefully chosen and controlled to achieve complete cure. The effects of incomplete cure on membrane properties is considered in the following section. Cure dependence It can be difficult

of membrane

lco%S

50

loo%A

Membrane Composition “=3

Fig. 5. Control of network structure - the number of siloxane units between crosslinks in silicone membranes as a function of membrane composition.

“F’

Partially cured

c

properties

to measure the properties of partially cured membranes when the curing reaction proceeds during the measurement. For this investigation, stable partially cured membranes were simulated by membranes prepared with lower cross-linking densities. This was found possible by using a pair of silicone polymers which crosslink by addition reaction, as in Fig. 1. By varying the ratio of components, it is feasible to achieve different degrees of crosslinking which simulate partially cured silicone membranes. Figure 5 illustrates that crosslinking densities of membranes can be controlled in the range where the number of siloxane units between crosslinks was 80 to 1900 units. Particularly for the membranes consisting of component A in amounts greater than 90%, a wide range of partial cures can be simulated using this method. Since both polymer components are silicone, varying their proportions did not significantly alter the polarity of the mem-

Fig. 6. The elasticity of silicone membranes as a function of crosslinking density. Full cure corresponds to 100 siloxane units between crosslinks. The membranes are less fully cured as the number of units between crosslinks increases.

brane, only its network structure. So any changes in the physicomechanical properties reflect differences in the extent of cure and not variations in physicochemical interactions between polymer chains or between polymer and drug. The elasticity of a partially cured membrane with 300 siloxane units or more between crosslinks decreases with increasing number of siloxane units between crosslinks (Fig. 6). Thus, it appears that incomplete curing results in a very extensible membrane that will lose its shape when it is removed from its mold or package. It will also creep under smaller stresses. These undesirable physicomechanical properties are due to the low degree of crosslinking in a poorly cured membrane. In a fully cured

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membrane the elastic nature of silicone polymer results form the flexibility of the silicone chains, as well as the crosslinks that hold the polymer network together. Without the crosslinks, the flexibility of the polymer chains produces a freely flowing liquid-type polymer with no elasticity. So, both the flexibility as well as the crosslinks constitute the elastic properties of silicone elastomers. Thus, incomplete curing lowers the elastic nature of silicone membranes. Perhaps one of the most important properties of a controlled release drug delivery device is the reproducibility of the release rate of drug from the rate-controlling polymer membrane. The data on the permeation of testosterone through the membranes (Table 3) indicate that the normalized permeation rate is not as dependent upon the crosslinking density of the silicone membranes as shown by the elastic properties of the membranes. The practical implication of these results is that a slightly undercured membrane will have virtually the same TABLE 3 Variation in the permeation rate of testosterone across silicone membranes with different crosslinking densities Number of siloxane units between crosslinks

Normalized permeation rateb (mg/cm*h)

79.2 ( 2.4)” 84.5( 5.4) 94.8( 1.8) 103.4(4.8) 108.5(4.2) 109.8(6.1) 115.0(7.0) 148.6(6.2) 280.7(8.6) 813.5t30.6) 1593.9(15.8)

0.189(0.008)' 0.197(0.013) 0.180(0.025) 0.202 (0.008) 0.184(0.014) 0.185 (0.025) 0.224(0.012) 0.225(0.008) 0.201(0.023) 0.205 (0.027) 0.244(0.024)

“Standard deviations are given in parentheses. bThere was no significant difference between the sample means (triplicate) as determined by Tukey’s Test where CY=o.o5 1151.

Siloxane Cham -o/,;;\O’<

,cH3 si-F3

“\ Hydrocarbon Chain

H ,,

Fig. 7. All trans conformation backbones.

of silicone and hydrocarbon

drug release properties as a fully cured membrane. So, the margins of process control may be wider without affecting the release profile of the device. However, this is not so for all polymers, such as hydrophilic polymethacrylate polymers [ 91. Silicone is a rather unique polymer. The key is again the flexibility of the polymer chains. More specifically, the flexibility is due to the low energy of rotation about the Si-0 bond, resulting from the partial polar nature of the bond [ 161. Another unusual feature of the silicone polymer is that its lowest energy conformation, the all trans state, yields a curved chain configuration rather than a straight zig-zag as seen in hydrocarbon chains (see Fig. 7). So, there exists a greater degree of freedom for the motion of the silicone backbone. In addition, even the fully cured silicone membrane is expected to have only one crosslink for every 100 siloxane units. This relatively low crosslinking density does little to impede the motion of silicone chains required to create sufficient space for a testosterone molecule to diffuse through the silicone network. Perhaps, there would be a decrease in the permeation rate of testosterone if the crosslinking density were higher. However, at the level of crosslinking densities of commercially available silicone elastomers, the permeability of the membrane is relatively insensitive to the variation in the extent of curing.

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ACKNOWLEDGEMENTS

The authors wish to express their appreciation to the American Foundation for Pharmaceutical Education for providing fellowship support and to Dow Corning Corporation for generously donating the silicone elastomer needed for this investigation.

7

8

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REFERENCES F.C. Kincl, G. Benagiano, and I. Angee, Sustained release hormonal preparations. I. Diffusion of various steroids through polymer membranes, Steroids, 11 (1968) 673-680. Y.W. Chien, Transdermal Controlled Systemic Medications, Marcel Dekker, New York, NY, 1987, Chapter 2. M. Kbadi and Y.W. Chien, Intravaginal controlled administration of flurogestone acetate: (III) Development of rate-control vaginal devices, Drug Dev. Ind. Pharm., 11 (1985) 1271-1312. Y.W. Chien, Novel Drug Delivery Systems, Marcel Dekker, New York, NY, 1982. E.L. Tan, J-C. Liu and Y.W. Chien, Controlled drug release from silicone-coated tablets: Preliminary evaluation of coating techniques and characteristics of membrane permeation kinetics, Int. J. Pharm., 42 (1988) 161-169. F.S. Rankin, The use of silicones for the controlled release of drugs, In: N.A. Peppas and R.J. Haluska (Eds.) Proc. Int. Symp. Controlled Rel. Bioactive Mater., Vol. 12, Controlled Release Society, Inc., Lincolnshire, IL, 1985, pp. 143-144.

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W.L. Robb, Thin Silicone Membranes - Their Permeation Properties and Some Applications, Ann. NY Acad. Sci., 146 (1968) 119-137. J.T. Ma, L. Wu, G.G. Qi, J.H. Lui, K.D. Kao, P.H. Tang, Y.L. Zhang and T.Z. Tong, Radiation crosslinked poly (vinyl methylsiloxane) for levonorgestrel delivery system, J. Polym. Sci., Part C: Polym., Lett., 26 (1988)195-199. Y.W. Chien and E.P.K. Lau, Controlled drug release from polymeric delivery devices (IV): in uitro-in uioo correlation on the subcutaneous release of norgestomet from hydrophilic implants, J. Pharm. Sci., 65 (1976) 488-498. R.H. Bogner, J-C. Liu and Y.W. Chien, Methods for determining partial solubility parameters of potential film-coating polymers, Int. J. Pharm., 42 (1988) 199209. K. Tojo, Y. Sun, M.M. Ghannam and Y.W. Chien, Characterization of a membrane permeation system for controlled drug delivery studies, AIChE J., 3‘1 (1985) 741-746. P.J. Flory and J. Rehner, Jr., Statistical mechanics of cross-linked polymer networks II. Swelling, J. Chem. Phys., 11 (1943) 521-525. A.M. Bueche, Interaction of Polydimethylsiloxanes with swelling agents, J. Polym. Sci., 15 (1955) 97-103. New product information: Silastic medical grade ETR elastomers, Dow Corning Corp., Midland, MI, 1982. P.J. Flory, V. Crescenzi and J.E. Mark, Configuration of the poly(dimethylsiloxane) chain. III. Correlation of theory and experiment, J. Am. Chem. Sot., 86 (1964) 146-152. L. Ott, An Introduction to Statistical Methods of Data Analysis, Duxbury Press, North Scituate, MA, 1977, 289 pp.