ELSEVIER Journal of Controlled Release 40 (1996) 55-65

journal of c o n t r o l l e d

r e l e a s e

Water uptake in to polyanhydride devices: kinetics of uptake and effects of model compounds incorporated, and device geometry

on water uptake

Eun-Seok Park a, Manoj Maniar b, Jaymin Shah a , *

Department of Pharmaceutical Sciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425. USA b Houghten Pharmaceuticals Inc., 3550 General Atomics Court, San Diego. CA 92121, USA

Received 16 May 1995; accepted 11 October 1995

Abstract

Polyanhydrides are known as surface eroding biodegradable polymers since they are hydrophobic, which is believed to prevent penetration of water into the bulk and hence only the labile bonds on the surface are hydrolyzed. We wanted to test the hypothesis that polyanhydrides, specifically poly(fatty acid dimer-sebacic acid; FAD-SA) undergo pure surface erosion. If P(FAD-SA) does indeed undergo pure surface erosion, very little water should be present in the device since the polymer is hydrophobic and hydrolyzed on contact with water. An understanding of water uptake is also necessary to predict the stability and release of the incorporated drug. The specific aims of this study were to establish the rate of water uptake into P(FAD-SA) devices of cylinder and disk shapes at various pH conditions, and to study the effect of loaded model drug compounds (having different molecular size, aqueous solubility and dissolution rate) on water uptake. The model compounds included: mannitol, inulin and stearic acid, loaded at 10% (w/w) in disk-shaped devices. Water uptake was estimated from the amount of tritiated water found in the devices after they were soaked and gently mixed with buffers (pH 1-9) containing tritiated water (1 /xCi/ml) at various time intervals. The results showed that water uptake by the device is a function of pH (pH 9 > pH 7.4 >>> pH 1-5). Significantly higher amount of water was taken up at pH 7.4 and 9.0 (8-9% (v /v ) for cylindrical devices, 15-25% (v /v ) for disk-shaped device in 2 weeks), compared to less than 5% (v /v ) uptake between pH 1 and 5. Disk-shaped devices showed a faster uptake rate compared to cylinder-shaped devices due to their higher surface area to volume ratio. The loaded compounds had no significant effect on either the water uptake profile or water uptake kinetics at all pH values examined. From the large amount of water (up to 20% (v /v) ) found in the devices at pH 7.4 and pH 9.0, it appears that P(FAD-SA) does not undergo pure surface erosion. The photomicrographs of the devices at various stages of water uptake showed channels on the rough surface indicative of bulk erosion rather than pure surface erosion.

Keywords: Biodegradability: Polyanhydride; Poly(fatty acid dimer-sebacic acid); Water uptake; Surface erosion; Drug delivery: Implant

1. Introduct ion

* Corresponding author. Tel. + 1 803 7925366; Fax + 1 803 7920759.

Biodegradable control led release systems using various types of natural and synthetic polymers such as polyanhydrides , poly(c~-esters), po ly(amino acids),

0168-3659/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0168-3659(95)00143-3

56 E.-S. Park et a l . / Journal of Controlled Release 40 (1996) 55-65

polyorthoesters, polyphosphazenes, poly(phosphate esters), have been studied extensively for drug deliv- ery [1-4]. Biodegradable polymers erode by two erosion mechanisms; homogeneous or bulk erosion, and heterogeneous or surface erosion [5]. In bulk erosion, water penetrates into the bulk of the poly- mer, resulting in degradation occurring throughout the polymer matrix at the same rate as exhibited by Poly(lactide-co-glycolide) copolymers [6-9]. This results in pores and channels in the matrix which makes it difficult to accurately control the rates of polymer degradation and drug release [8,9]. There- fore, predicting and controlling the release kinetics of drug from bulk eroding polymers is very difficult, and thus drug release occurs after a lag time fol- lowed by large burst rather than being continuous [6-10].

Polyanhydrides are believed to undergo pure sur- face erosion due to the high lability of the anhydride bonds on the surface and the hydrophobicity, which prevents water penetration into the bulk [11]. Achiev- ing such a differential hydrolysis of surface over the bulk requires the rate of hydrolytic degradation on the surface to be much faster than the rate of water penetration into the bulk. Therefore, the ideal poly- mer would have a hydrophobic backbone to prevent water uptake, but have a water labile linkage to result in surface erosion. Secondly, if water cannot penetrate into the bulk matrix, then the hydrolytically labile drug is protected from the exterior aqueous environment and may result in increased stability of the incorporated drug. Because of this beneficial effect, polyanhydrides are being evaluated as carriers for water soluble and labile peptides and proteins [12,13].

A new class of aliphatic copolyanhydrides, poly(fatty acid dimer-sebacic acid) (P(FAD-SA)), synthesized from hydrophobic dimers of erucic acid and sebacic acid was reported to have desirable erosion and physicochemical characteristics [14,15]. This copolymer can be prepared using different ra- tios of the monomers to achieve the desired degree of hydrophobicity, higher percentages of FAD indi- cating a more hydrophobic copolymer, and is be- lieved to undergo surface erosion. Since P(FAD-SA) are extremely hydrophobic, the rate of water uptake or water penetration will affect the rate of drug release. If P(FAD-SA) undergo pure surface erosion,

there should not be any water present in the device. Therefore, to test if P(FAD-SA) undergo pure sur- face erosion, water uptake was studied into cylinder- and disk-shaped devices of P(FAD-SA, 50:50 w / w ) at various pH values. The specific aims of this study were to establish the rate of water uptake into P(FAD-SA, 50:50 w / w ) polyanhydride devices of cylinder and disk-shaped at various pH conditions, and to study the effect of loaded model drug com- pounds (having different molecular size, aqueous solubility and dissolution rate) on water uptake.

The study of water uptake by measuring the weight gain of the soaked device may not reflect the amount of water taken up, since the device loses weight due to erosion, and the additional problem encountered is the difficulty in accurately estimating a small gain in weight of the device due to water uptake [16]. Another method is to measure the up- take of a highly water soluble dye into the device as a measure of water uptake by the device presoaked in the aqueous dye solution [17]. However, in this method, one cannot eliminate the possibility of spe- cific interaction between dye and the polymer. Therefore, we studied water uptake by soaking and mixing the device in buffers prepared with diluted tritiated water and measuring the radioactivity levels in the device at various time intervals. Since the radioactivity is solely due to tritiated water, this method unequivocally establishes the amount of wa- ter taken up by the device.

2. Materials and methods

2.1. Materials

Poly(fatty acid dimer:sebacic acid) [P(FAD:SA. 50:50 w/w)] copolymer and placebo devices in the form of a cylinder (1.3 cm × 0.33 cm) were suppliec by NOVA Pharmaceutical Inc. (Baltimore, MD) Tritiated water (100 mCi /ml ) was purchased frorr ICN Biochemicals (Irvine, CA) and used to prepare radioactive (hot) buffer (1 /zCi/ml) after dilutior with cold buffer. Scintiverse LC ®, tetrahydrofuraz (THF) and HC1 were purchased from Fisher. o-Man nitol, inulin and stearic acid were purchased fron Sigma (Sigma Chemical Co., St. Louis, MO). All th~

E.-S. Park et al. / Journal of Controlled Release 40 (1996) 55-65 57

buffer salts were obtained from Curtis Matheson Scientific (Houston, TX).

2.2. Methods

2.2.1. Preparation of radioactive (hot) buffer solu- tions

A solution of pH 1 was prepared using 0.1 N HC1, while pH 3, 5, 7.4 and 9 were obtained using various ratios of KH2PO 4 and K2HPO 4 with adjust- ment of the final pH by addition of KOH and/or H 3 P O 4. The buffer concentration at each pH was 0.1 M. All buffer solutions were filtered through 0.8 /xm membrane filters and degassed under vacuum. Then, 50 /zl of 10 m C i / m l (500 /zCi) tritiated water was pipetted into 500 ml volumetric flasks and the vol- ume made up to 500 ml with each of the above-men- tioned buffers, respectively. The radioactivity level of the hot buffer was l ~ C i / m l and was confirmed by measuring counts (dpm) by scintillation counting using a Beckman LS 8100.

2.2.2. Preparation of the devices The placebo devices in the form of cylinder with

length and radius of 1.3 and 0.333 cm, respectively, weighing 200 mg were received from NOVA Phar- maceutical, Inc. Circular disk-shaped devices of 0.41 cm radius and 0.1 cm thickness were prepared by incorporating the model compounds in polyanhy- dride by the melt casting technique. The polymer was melted on a Teflon coated glass plate heated to 67°C on a hot plate, and the model compound dis- persed uniformly in the melt. The dispersion was surrounded by a 0.1 cm thickness cardboard shim and another Teflon covered glass plate placed on top of the melt. The two glass plates with the shim in between them were pressed together using a 2 kg

weight of lead brick and allowed to cool to room temperature. On cooling, the polymer solidified and formed a film, when the two plates were separated. A disk of the required radius was cut off the film with a cork borer and carefully placed in vials flushed with nitrogen gas and the vial placed in a freezer immediately to prevent any degradation of the polymer. Placebo devices were also prepared as controls. The radius, thickness and weight of each device were measured for each batch of devices prepared. A number of devices had been prepared with very reproducible dimensions as listed in Table 1. To verify uniform dispersal of the model com- pounds in devices (content uniformity), a few of the batches of devices were prepared with radioactively (C 14) labeled model compounds. These incorporated hot model compounds were extracted from the de- vices and analyzed for model compounds to estimate the content uniformity of the devices. The results of content uniformity study showed close to 100% in- corporation with very small variability as seen in Table 1.

2.2.3. Determination of water uptake into devices at various pH ualues

The water uptake study was conducted on cylin- der and disk-shaped placebo devices and disk-shaped devices loaded with 10% of mannitol, inulin, and stearic acid, at pH 1, 3, 5, 7.4 and 9. At the beginning of the experiment, a device was placed in each vial containing 20 ml buffer which was spiked with enough tritiated water to achieve a radioactivity level of 1 /~Ci/ml. Two additional vials, one with cold buffer and the other with hot buffer, served as controls. The device was removed from the appropri- ate vial at 0, 1, 3, 7 days and at the end of 2, 3, and 4 weeks. The device was wiped dry, lightly with an

Table 1 Dimensions of placebo and 10% w / w model compound loaded P(FAD-SA, 50:50 w / w ) disk-shaped devices

Specifications Placebo Mannitol Inulin Stearic acid device device device device

Weight (mg) 28.67 + 0.22 29.27 + 0.09 27.73 _+ 0.36 27.59 _+ 0.43 Radius ( r ) (cm) 0.41 _+ 0.004 0.41 + 0.003 0.41 _+ 0.004 0.41 _+ 0.004 Thickness (h) (cm) 0.10 + 0.003 0.10 _+ 0.003 0.10 _+ 0.003 0.10 + 0.003 Content uniformity (% of label) 98 + 5 95 _+ 7 100 _+ 4

n = 6; volume (cm 3) = 7r X r 2 × h. 0.053 cm3; surface area (cm 2) = [(~- X r 2 X 2) + (2 × ~" X r × h)], 1.31 em 1.

58 E.-S, Park et al. / Journal of Controlled Release 40 (1996) 55-65

absorbent paper to remove the adsorbed water. The device was then dissolved in 1 ml THF by sonica- tion. The clear solution so obtained was diluted with Scintiverse, the scintillation cocktail, and the ra- dioactivity of the solution measured with a Beckman Scintillation Counter, LS 8100 with automatic quench correction. At each sampling period, the solution in the vial, and the cold and hot buffers of the control vials were also treated similarly, and the radioactiv- ity measured. The counts were corrected for quench- ing by running a quench curve using the tritium standards, and the volume of water taken up by the device was calculated. The experiments were run in triplicate at all five pH values.

2.2.4. Estimation of amount of water taken up, and the kinetics of water uptake

The counts (dpm) after quench correction were converted into amount of water (ml) taken up based on the relationship: 1 /xCi = 2.2 × 10 6 dpm, and knowing the radioactivity level of hot buffer (1 /xCi/ml). The water uptake profiles were evaluated kinetically to estimate the rate constants for water uptake. First order water uptake rate constant was obtained using the following equation:

3. Results

3.1. Determination of water taken up into the devices

Visual observation of the devices at various sam- pling times showed that at pH 1, 3 and 5, the devices were slightly swollen yet intact until 4 weeks. In contrast, at pH 7.4 and 9, the devices were consider- ably more swollen, some of them developed cracks, and layers of the polymer peeled off into the solu- tion. In addition, at pH 7.4 and 9, the surface of devices was very sticky. The radioactivity level of the cold buffer was about 70 dpm/ml while that of hot buffer of the control about 1.2 × 106 dpm/ml throughout the experimental duration, indicative of a properly controlled experiment. The preliminary findings were published earlier [18]. The average values (n = 3) of the amount of water taken up by the cylinder and disk-shaped devices at various pH values are plotted as a function of time in Figs. 1 and 2a-d. As seen from these figures, water was taken up rapidly in the first 3 days at all pH values. There was a significant difference in the rate and the pattern of water uptake under different pH condi- tions. At pH 1-5, water was taken up very slowly by

A ( t ) ( m l ) = A o ( m l ) × ( 1 - e ~°.')

where t is time (day), A 0 (ml) is the maximum amount of water that will be taken up by the device, and kup (day 1) is the first order water uptake rate constant. In addition, under some conditions, water uptake was better described by zero order kinetics.

2.2.5. Photomicrography of devices The objective of microscopic examination of de-

vices was to visually observe the effect of water on the surface of the devices. If the devices are undergo- ing heterogeneous (surface) erosion as believed, the surface of the devices should be smooth, however, homogeneous or bulk eroding devices are character- ized by formation of pores and channels throughout the matrix [8]. The devices shaken with buffers of various pH values were removed from the vials and observed microscopically and photographed.

10 0 05

8 004

6 003

4 0.02 <-.

2 0.01

O I I t t t 0 0 7 14 21 28

Time (days)

÷ p H 1.0 -l~pH 3.0 -A-pH 5.0 [-~-pH 74 m-pH 9.0 Cyl nder-Placebo

Fig. 1. Wate r uptake profiles o f cy l inder shaped placebo devices

at var ious p H condi t ions (n = 3).

E.-S. Park et al. / Journal of Controlled Release 40 (1996) 55-65 59

the device as indicated by a very slight linear in- crease in the volume of water found in the device. In fact, at maximum, only 5% ( v / v ) of water was taken up by the devices in 4 weeks. In contrast, at pH 7.4 and 9, the amount of water found in the device continued to increase till 4 weeks and may continue

to do so for the cylinder-shaped placebo devices. At the end of 4 weeks, the amount of water in the cylinder-shaped device was approximately 8-9% (v /v) , around 2-fold that at pH 1-5. Similarly, disk-shaped placebo devices showed that the water uptake was also slow at pH 1-5 and only a maxi-

=o

3:

25 0.012

A

20

15

10

5

0 ~ 7 i4 21 28

Time (days)

"~-pH 1.0 "~'pH3.0 -kpH5.0 ] i

+ pH 7.4 l p H 9.0 Disk-Placebo]

0.01

0.008

0.006 ~

0004 -~

0.002

2O

B

15

10

5

oj 7 14 21 28

Time (days)

-O-pH 1.0 "~'pH 3.0 -A-pH5.0

+ pH 7.4 !1- pH 9.0 Disk-Mannito

0.01

0.008

0.006

0.004

0.002

<.

25

20

I0

Ol 0

I I I I

7 14 21 28

Time (days)

-e-pH 1.0 "~'pH 3.0 -~rpH 50 -~- pH 7.4 -II-pH 9.0 D sk-Inu in

0.014

0.012

0.01

0.008

0.006

0,004

0.002

0

25

D

2O

15

11 ll/ . - a .

7 7 ? , 7 14 21 28

Time (days)

-O-pH 10 -O-pH 3.0 -A-pH 5,0

--pH 7.4 m pH 9.0 Disk-Stearic acid

0,014

0.012

0,01

0.008

0.006 ~"

-ff 0.004

0.002

Fig. 2. Water uptake profiles of disk-shaped (a) placebo devices, (b) 10% ( w / w ) mannitol loaded devices, (c) 10% ( w / w ) inulin loaded devices, (d) 10% ( w / w ) stearic acid loaded devices, at various pH conditions.

60 E.-S. Park et al. / Journal of Controlled Release 40 (1996) 55 65

mum of 4% ( v / v ) water uptake was observed at the end of 4 weeks. However, at pH 7.4 and 9.0, a significantly higher amount of water was taken up ( 1 5 - 2 0 % ( v / v ) in 2 weeks). From Figs. 1 and 2a, it appears that the absolute amount of water taken up by the cylinder-shaped devices at pH 7.4 and pH 9.0 is more than the amount found in the disk-shaped devices. However, when normalized by the volume of device, % ( v / v ) of water found in disk-shaped devices was higher than in the cylinder-shaped de- vices. The rate of water uptake into disk-shaped devices is faster than that into cylindrical devices at pH 7.4 and 9.0, respectively. Although the water uptake profiles were very similar in overall shape, the amount of water taken up by the placebo disk- shaped devices was significantly higher than that for cylinder-shaped devices.

Loaded compounds (mannitol, inulin and stearic acid) did not have a significant effect on water uptake as seen in Fig. 2 a - d . The water uptake properties of the devices also remained unchanged with respect to the pH. The water uptake profile at pH 9.0 was highest fol lowed by pH 7.4 and then by pH 1-5. Under identical pH conditions, the uptake profiles of model compound loaded devices showed a similar pattern of water uptake to placebo disk- shaped devices as shown in Fig. 2 a - d for pH 7.4 and 9.0.

3.2. Kinet ics o f water uptake

For cylinder-shaped placebo devices, the data at pH 1, 3 and 5 were explained better by zero order kinetics whereas the data at pH 7.4 and pH 9 were explained better by first order kinetics. The kinetic parameters, rate of water uptake, or the rate constant were estimated and are reported in Table 2. As seen from Table 2, the rate of water uptake was constant and only 0.0003 m l / d a y between pH 1 and 5, indicating very slow water uptake at the acidic pH. Zero order rates of water uptake at pH 7.4 and 9.0 were also calculated from the initial linear portion of the water uptake profiles and listed in Table 2, which were 0.0012 and 0.0018 m l / d a y , respectively. Thus, water uptake was at least 4-times faster at pH 7.4 and 6-times faster at pH 9.0, suggesting that pH has significant influence on water uptake.

Water uptake profile of disk-shaped devices ap-

Table 2 Kinetic parameters for water uptake of P(FAD-SA, 50:50 w/w) cylinder-shaped placebo devices at various pH conditions at room temperature

pH ku°p kup (day I) A 0 (ml)

1.0 0.00035 +0.00021 3.0 0.00035 +0.00014 5.0 0.00030-+ 0.00004 7.4 0.00115_+0.00007 ~' 0.06494-+0.01425 0.04337_+0.0050 9.0 0.00176 + 0.00004 a 0.08351 _+ 0.00587 0.04397 _+ 0.0023

n = 3; k°p, zero order water uptake rate (ml/day): kuv, first order water uptake rate constant (day ~). First order uptake rate con- stant (day ~ ) obtained using the entire range of data fitted to the following equation: a ( t ) ( m l ) = a 0 ( m l ) X ( l - e ~:up~) where t = time (days) and A 0 is the maximum amount of water that will be taken up by the device.

Obtained using initial linear portion of water uptake profiles.

peared to follow first order kinetics under all pH conditions and the rate constant for water uptake of model compound loaded and placebo disk-shaped devices were calculated. Although the rate constant for water uptake failed to follow any relationship with pH or the model compound present in the devices, A o, the maximum amount of water that will be taken up by the devices followed a systematic pH-dependent trend as shown in Fig. 3a. A 0 was independent of pH or the model compound loaded devices between pH 1 and 5 and was approximately 4% ( v / v ) of the device. However, with increase in pH, at pH 7.4 and 9.0, the A 0 increased in a linear fashion for placebo as well as model compound loaded devices. The zero order rate of water uptake calculated from the initial linear portion of uptake profiles of each model compound also followed a similar pattern as shown in Fig. 3b.

3.3. Photomicrography o f devices

Disk-shaped placebo and model compound loaded devices were observed and photographed under a microscope after soaking in buffers for various time intervals. Devices soaked in pH 1-5 buffers did not reveal any significant morphological changes. How- ever, devices soaked in pH 7.4 and 9.0 demonstrated dramatically the effect of erosion on device surface. Fig. 4 a - e depicts photomicrographs of a typical

E.-S. Park et al. / Journal of Controlled Release 40 (1996) 55-65 61

placebo and model compound loaded devices after soaking in pH 7.4 buffers for 3 weeks. As seen clearly, channels not present at the beginning, are visible on the surfaces of the devices. Also there

appear to be islands of material not dissolved in the devices. The stearic acid device showed granular material dispersed uniformly, indicative of undis- solved stearic acid as seen in Fig. 4e.

Ao (Maximum amount &water taken up in ml) % v/v 0.016 30

0014

0012

0010

0.008

0.006

0004

0.002

0000

0.0025

mPlacebo

~Mannitol

[Z]Inulin

EE]Stearic acid

pH 1 0 pH 3.0 pH 5.0 pH 7.4

Zero order water uptake rate (nil/day)

A

~q

pH 9.0

26.25

22.5

18.75

15

11.25

7.5

3.75

0

0.0020

00015

O.OOlO

00005

0.0000

B

pH 1 0 pH 3.0 pH 5.0 pH 7.4 pH 9.0

Fig. 3. Effect o f pH and model compounds on (a) A 0, the

m a x i m u m amount of water that was taken up by the disk-shaped

devices, and (b) zero order water uptake rate into disk-shaped

devices.

4. Discussion

The pH-dependent water uptake into polyanhy- dride can be explained based on the labile nature of anhydride bond. Hydrolysis of polyanhydride is sig- nificantly higher at alkaline pH than at acidic pH and the rate constant for hydrolysis increases in a log scale with increase in pH [14,15]. Therefore, hydrol- ysis of anhydride linkage should proceed at signifi- cantly higher rates at pH 9.0 followed by pH 7.4 and very little hydrolysis at pH 1-5. Therefore, higher water uptake at pH 7.4 and 9.0 correlates very well with pH-dependent hydrolysis of anhydride linkages. As seen in Table 2 and Fig. 3a-b, the rate of water uptake is close to zero at pH 1-5 as would be expected because of very slow hydrolysis of polyan- hydride in acidic conditions. In addition, even with slow degradation, the degradation products, sebacic acid and fatty acid dimer would be unionized and insoluble in the buffer at the acidic pH. Thus, they would form a barrier for water to penetrate further into the matrix. The observed rate at pH 9.0 is 1.2-times higher than at pH 7.4, which is 4-times higher than at pH 1-5. This can be explained on the basis that anhydride linkage undergoes base-cata- lyzed hydrolysis, and as the polymer hydrolyzes, the degradation products, FAD and SA would be ion- ized, and only sebacic acid will dissolve in the buffer. Free fatty acid dimer (a C44 diacid) which is extremely hydrophobic and insoluble in the buffer will form a layer on the surface of the device which will slow down the penetration of water into the matrix as a function of time. Therefore, when se- bacic acid is released and depleted completely, de- vice is then primarily composed of FAD. Then, there is no more water uptake into device because of the complete hydrolysis of polymer in the device. This also explains the first order uptake kinetics observed for water uptake, since eventually the device will be composed of only FAD with pores and channels filled with water but of a fixed finite volume. The amount of water ultimately found in the device, A 0,

62 E.- S. Park et al. / Journal of Controlled Release 40 (1996) 55-65

E.-S. Park et al. / Journal of Controlled Release 40 (1996) 55-65 63

Fig. 4. Photomicrographs of the surfaces of (a) intact placebo device, and the following disk-shaped devices soaked in pH 7.4 buffer for 3 weeks: (b) placebo device, (c) 10% (w/w) mannitol loaded device, (d) 10% (w/w) inulin loaded device, (e) 10% (w/w) stearic acid loaded device.

should therefore correlate with erosion and hence pH. As a rtesult of the greater amount of erosion, more sebacic acid leaves, creating more pores and channels to increase the void volume for water to penetrate. In contrast, the rate constant for water uptake should be related to the diffusion coefficient of water in the pores and channels of the device and hence should be relatively independent of pH of erosion medium or the model compounds loaded in the devices. This is supported by the data presented in Table 2 and Fig. 3a and b.

Due to the high amount of water (20% (v/v))

found in the devices, the devices may be undergoing bulk erosion rather than surface erosion at pH 7.4 and pH 9.0 because under pure surface erosion, a significant amount of water should not be found inside the devices as mentioned earlier in section 1. Similarly, a large amount of water was found to be taken up by poly(lactide-co-glycolide) at 37°C at pH 7.4 [8]. This was attributed to formation of pores and channels following polymer degradation [8]. Since poly(lactide-co-glycolide)s are known to undergo bulk erosion, it can be said similarly that P(FAD-SA) is undergoing bulk erosion. This scenario for erosion

64 E.-S. Park et al. / Journal of Controlled Release 40 (1996) 55-65

of polyanhydride was also supported by the physical evidence, the observation of channels and pores on device surface as seen in the photomicrographs veri- fying that the devices are not undergoing surface erosion. This microscopic observation not only elim- inates the possibility of surface erosion but also supports our earlier version of device erosion, i.e. polymer hydrolysis, release of sebacic acid, leaving behind islands of FAD surrounded by pores and channels, through which water would penetrate into the device and simultaneously drug will be released through water filled pores and channels.

The loaded compounds (mannitol, inulin and stearic acid), although quite different in aqueous solubilities and molecular weight, had no influence on water uptake over the entire pH range of 1-9. This suggests that water uptake is primarily related to polymer hydrolysis, and not to the nature of compound incorporated. If the loaded compounds were insoluble, and loaded at higher loads, they might slow device erosion and hence water uptake would also be affected.

The melt-casting technique produced devices of very reproducible dimensions (Table 1), which is essential for water uptake study since it will depend upon the surface area of the devices exposed to water. The effect of surface area of the device or geometry on water uptake can be explored by com- paring the results obtained with the disk-shaped and cylindrical devices. As seen in Figs. 1 and 2a, the disk-shaped device showed a higher water uptake than the cylindrical device. Since the surface area to volume ratio (SA/V) of disk-shaped device is larger than that of the cylindrical device (3.27:1), it has more surface area per unit volume of the device exposed for contact with water for hydrolysis and hence uptake. Therefore, disk-shaped devices with higher S A / V ratios resulted in the faster uptake rate for water. The above conclusion can also be sup- ported by the observation that water appeared to stop penetrating into the disk-shaped device after 2 weeks at pH 9.0, meanwhile water uptake continued until 4 weeks for the cylindrical device at the same pH. Because of the higher uptake rate and the smaller volume of the disk-shaped device, hydrolysis of the polyanhydride device was completed in 2 weeks and the device was then composed primarily of FAD. Meanwhile the cylindrical device has a larger vol-

ume and showed a slower rate of water uptake. Therefore, hydrolysis could have continued until 4 weeks at pH 9. Moreover, visual observation of the cross-section of the cylinder-shaped devices after 3 weeks at pH 9.0 showed that the inside of the devices was still intact unlike the completely swollen disk-shaped device.

5. Conclusions

The results show that water uptake by the device is a function of pH (pH 9 > pH 7.4 >>> pH 1-5), with a large amount of water taken up at pH 7.4 and 9.0 (8-9% (v/v)) for cylindrical devices, 15-20% (v/v)) for disk-shaped device in 4 weeks). Water uptake was directly proportional to the S A / V of device as disk-shaped devices showed a faster uptake rate compared to cylinder-shaped devices, but it was unaffected by the physicochemical nature of the loaded compounds at all pH values. Therefore, water uptake occurs subsequent to polyanhydride hydroly- sis and from the large amount of water found in the devices at pH 7.4 and pH 9.0, it suggests that P(FAD-SA) is not undergoing pure surface erosion. In addition, the photomicrographs of the devices at various stages of water uptake showed channels on a rough surface indicative of bulk erosion rather than pure surface erosion.

Acknowledgements

We would like to thank Nova Pharmaceutical Inc. for supplying P(FAD-SA: 1:1 w / w ) polymer. This study was supported in part by the Medical Univer- sity of South Carolina Institutional Research Funds of 1991-1992.

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[3] J. Heller, Biodegradable polymers in controlled drug deliv- ery, CRC Crit. Rew Ther. Drug Carrier Systems 1 (1984) 39-90.

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