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UV induced crosslinking of polyvinylalcohol and hydroxypropyl-methylcellulose with sodium-benzoate.


Sodium benzoate is used primarily as an anti-microbial preservative in cosmetics, foods and pharmaceuticals. It decomposes under UV light with an average wavelength of 254 nm and is then able to induce a crosslinking reaction in for example polyvinylalcohol (PVAl) or hydroxypropylmethyl-cellulose (HPMC) [13, 14]. The mechanism of this crosslinking process is not completely elucidated.

The crosslinking decreases the water-solubility of the PVAl and HPMC and therefore the UV crosslinking of these water-soluble polymers could be a method to induce a lag-time before the coating dissolves. In this part we describe the experiments to determine the suitability of crosslinked HPMC and PVAl as delayed release coatings.


The experimental procedure is as follows: low viscosity grades of HPMC (HPMC 5, Sigma-Aldrich, USA) or PVAl (Airvol PVAl 103, Air Products, The Netherlands) are dissolved in demineralised water. After the polymers were totally dissolved 3-w/w% of sodium-benzoate (Sigma-Aldrich, Milwaukee, USA), based on the dry polymer weight, is dissolved in the solution. Pellets consisting of 37.5-w/w% MCC and 65.5-w/w% sodium chloride in the size range of 0.60-0.71 mm (PVAl experiments) and 0.85-1.2 mm (HPMC experiments) are coated with this solution in a fluid bed. The coated pellets were dried in an oven at 60 ºC for 12 hours and cured under an UV lamp in the same way as the pellets coated with Eudragit L30D55.

Release experiments

In figure 5.17 the result is given for the PVAl coated pellets. As can be seen the curing process does not increase the lag-time. However, although the lag-time was not increased, the curing process did succeed because under the microscope it was clearly seen that a hydrogel layer is formed around the UV-cured pellets, which was not seen around the unUV-cured pellets. Also free films produced from UV crosslinked PVAl showed a swelling behaviour instead of dissolving in water.

Also in figure 5.17 the result is given for an experiment with a HPMC coating. Also here the UV-crosslinking does not increase the lag-time.

However additional experiments with free films showed that, as with the PVAl films, the solubility of crosslinked HPMC films is decreased considerably when compared with films without crosslinking.







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Figure 5.17 Results release experiments on pellets in the size range 0.6-0.7 mm coated with HPMC and PVAl coatings, influence UV-curing on release properties.

The most probable reason for the short lag-times of the UV cured HPMC and PVAl coatings is the fact that the UV cured coating swells very rapidly in water which causes a drastic decrease in the mechanical properties of the coating. Therefore only a low internal pressure in the coated pellet induced by transport of water through the film is enough to rupture the coating.

This is confirmed by experiments with free films. Free films of UV crosslinked HPMC were placed in-between a compartment with pure water and one with a certain osmotic pressure. In these experiments 50 µm thick films (both PVAl and HPMC) can only withstand the osmotic pressure of a 0.005 M sodium chloride solution for a few seconds.

Concluding it can be said that the water solubility of low viscosity PVAl and HPMC films can be decreased by UV curing but these coatings take up water very rapidly and thus swell very rapidly. This rapid swelling increases the water permeability and decreases the mechanical properties in such an extent that a delayed release cannot be obtained with these coatings.

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In the previous paragraphs we decreased the solubility of the coatings by crosslinking the polymer physically or chemically. In the next part we


adopt a different strategy, we coat particles with a water-insoluble film-former while adding a water-soluble compound to the coating to control the release properties. We do this by melting the water-insoluble film-former and dissolving the water-soluble compound in this melt. The molten solution is then applied on spherical particles by fluid bed coating.



Myristic acid (MA, C14H28O2) is a water-insoluble fatty acid with a melting point of 50 ºC. Sodium stearate (NaS, C18H35NaO2) is a water-soluble surfactant that dissolves in molten myristic acid at approximately 75 ºC. The maximum solubility of sodium stearate is 2 parts sodium stearate in 3 parts myristic acid when the temperature of the melt is 70 to 80 ºC. Higher percentages of sodium stearate can only be dissolved at higher temperatures.

The procedure for coating pellets in a fluid bed from a melt is as follows:

the myristic acid is molten and the sodium stearate is added to the melt and dissolved by vigorous stirring. The molten solution is sprayed onto the pellets by transporting the melt trough heated tubes into a heated pneumatic nozzle (figure 5.18) by means of a single rotor screw pump (Monopomp type EDD, Daurex GmbH, Germany). The atomizing air is also heated to prevent premature solidification of the melt in the nozzle.

The fluidization air is heated just below (5 to 10 °C) the melting temperature of the coating melt solution. We found that if the temperature fluidization air was far below (> 10 °C) the melting temperature of the coating material the produced coating was very porous. Another effect at lower temperatures was that a considerable amount of coating material was spray cooled and deposited on the walls of the fluid bed. If the temperature of the fluidization air was well above (> 10 °C) the melting temperature of the coating severe agglomeration of the pellets would occur.

Figure 5.18 Schematic representation experimental set-up hot melt coating experiments.


Release experiments

In figure 5.19 the release curves for two coating experiments are given for coating solutions with 2:1 and 3:2 mass ratios of myristic acid and sodium stearate. The cores consisted of 37.5-w/w% MCC and 65.5-w/w% sodium chloride in the size range of 0.6-0.85 mm. The formulation gives a lag-time at reasonable coating levels but the release after the lag-time is rather slow i.e.

there is not a perfect pulse release. Increasing the level of the water-soluble sodium stearate in the coating decreases the lag-time.

The release mechanism of this formulation was investigated under the microscope and with release experiments conducted with single pellets. The result of measuring the release of single pellets from the formulation denoted with the open triangles in figure 5.19 (15-w/w% or 32 to 38 micron 2:1 MA:NaS coating) is given in figure 5.20. Some light microscope images of the same formulation immersed in water are given figure 5.21.

From the release of single pellets it is seen that the individual pellets give a pulse release but with a large deviation in the lag-time. The images in figure 5.21 show that the release is triggered by the mechanical failure of the coating. Thus the release mechanism is controlled by the mechanical failure of the coating, most probably caused by the increase of volume of the core.






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Figure 5.19 Results release experiments on pellets (0.6-0.71 and 0.71-0.85 mm in diameter) with coatings consisting of 2:1 and 3:2 mass ratios myristic acid (MA): sodium stearate (NaS).







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Figure 5.20 Single pellet release experiments on a formulation coated with 12-w/w% or 28 to 34 micron 2:1 MA:NaS coating.

Figure 5.21 Photographs of a single pellet coated with 12-w/w% or 28 to 34 micron 2:1 MA:NaS coating immersed in water.

To investigate the water uptake properties of this coating gravimetric water sorption experiments were carried out; the results are given in figure 5.22 and figure 5.23. From these figures it can be seen that the coating only takes up a very small amount of water. From the experiments it was also seen that a free film of the material remains almost intact when immersed in water.

When a film is dried after it is brought in equilibrium with pure water over prolonged periods of time only 0.8 w/w% of the coating is dissolved.


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Figure 5.22 Water sorption curves for 2:1 a myristic acid : sodium stearate film, pure myristic acid and pure sodium stearate.






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Figure 5.23 Pure water uptake vs. time for a 2:1 myristic acid:sodium stearate coating.

Since the coating does not take up much water and does not dissolve or partly dissolve when it is immersed in water the diffusion of water through the material should be very slow and thus the lag-time in the release should be very long. However the lag-time of the formulation is only a few minutes


which can be explained with SEM photo’s of the surface of a formulation with a 2:1 sodium stearate:myristic acid coating. These SEM photos showed that most of the coated granules show little holes or cracks in the coating (figure 5.24). Through these holes water can be taken up much faster than through the coating and thus the lag-time is decreased considerably. This could also explain the large deviation in the lag-time of

the individual pellets since the distribution and size of the irregularities in the coating will be random and thus cause a random distribution of the lag-time.

Concluding we can say that although a large part of the coating is water-soluble the release mechanism is not controlled by the dissolution of this water-soluble compound.

The release mechanism of this formulation is most probably controlled by the amount of irregularities in the coating. This makes this formulation only moderately successful in inducing a pulse release of its contents.

Furthermore, since that this random

distribution of irregularities is very difficult to predict there was no mathematical model developed to predict the release time.


Experimental & Release experiments

The experiments were set up in the same way as the MA/NaS experiments, the soluble compound in this case being polyethyleneglycol (PEG) and the insoluble compound stearylalcohol (1-octadecanol, chemical formula C18H38O, abbreviated as SA).

In preliminary experiments large cores (10 mm in diameter experimental procedure see chapter 4) were coated. In figure 5.25 the release profiles are given for large cores coated with different mixtures of PEG and stearylalcohol.

The lag-time induced by these coatings increase with increasing percentage of stearylalcohol in the coating.

In figure 5.26 the result is given for small pellets (consisting of 37.5-w/w% MCC and 65.5-37.5-w/w% sodium chloride in the size range of 0.71 to 0.85 mm) coated with different levels of 1:1 SA:PEG. Compared to the large pellets experiments in figure 5.25 the smaller pellets are far less efficient in terms of the coating thickness and the resulting lag-time.

Figure 5.24 SEM photo of a

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Figure 5.25 Release experiments for large cores (diameter app. 10 mm) coated with a mixture of PEG6000 and stearylalcohol. The PEG:SA ratio is based on the mass of the coating.






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Figure 5.26 Release curves for pellets (composition: 37.5-w/w% MCC 65.5-w/w% NaCl, diameter: 0.7-0.85 mm) coated with 1:1 SA:PEG6000. Influence coating level.


Figure 5.27 SEM photographs of pellets coated with 1:1 SA:PEG6000, overview one whole pellet on the left. Detail of the coating on the right.

The reason for this is depicted in figure 5.27 with SEM photos of the surface of the coated small pellets. It is seen that the coating is very irregular and contains many holes, while the larger pellets (not shown here) have very smooth surfaces. Therefore water can be transported very fast through the coating of the small pellets to the core. This is confirmed by single pellet release experiments (figure not shown) which show that a large percentage of the pellets do not have a lag-time.The relatively high viscosity of the molten PEG6000 (1000 cSt at 60 ºC) makes it difficult to atomize the melt with a pneumatic nozzle. Therefore the droplet size of the atomized melt will be large compared to the size of the core resulting in an irregular surface. An attempt was made to solve this problem by

using a low molecular weight PEG (PEG1000) with a melt viscosity of 100 cSt at 60 ºC.

The coating quality was somewhat improved by incorporating PEG1000 as shown in figure 5.28. However the PEG1000 formulations failed to give a lag-time (figure not shown).

This is probably due to the fact that PEG1000 is more readily soluble in water than PEG6000 [15]

combined with the fact that the coatings on the pellets are still not flawless.

Figure 5.28 SEM photograph of a pellet coated with 1:1 SA:PEG1000.


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The formulations discussed in this chapter were all partly water-soluble or formed a hydrogel when immersed in water. From the hydrogel forming formulations (physically crosslinked calcium alginate and chemically crosslinked PVAl, HPMC and Eudragit L30D55) only the Eudragit L30D55 coating gave the desired release characteristics.

When we investigated the release mechanisms of these coatings it was found that the calcium alginate coating swells very fast when immersed in water. This is due to the fact that this material has a high affinity for water even at low water activities. The crosslinked low molecular weight PVAl and HPMC coatings also swell fast and have poor mechanical properties when immersed in water. These three crosslinked materials are not suitable to achieve the desired release properties.

The Eudragit coating swells slower and only at higher water activities and is thus more successful in inducing a lag-time. Creating a semi-IPN of the polymer and a poly-functional molecule decreases the water solubility of the Eudragit coating. The crosslink reaction is induced by UV-light. Both the coating thickness and the duration of the UV crosslinking time can be used to adjust the lag-time. When the Maxwell-Stefan diffusion coefficients are calculated for the crosslinked Eudragit coating an increase in the diffusion coefficients is found at higher water contents. The mathematical model predicts that the diffusion of water is rate-limited by the relaxation of the polymer chains and by the diffusion of water in the swollen part. The model gives a good estimation of the lag-time.

The formulations with a coating consisting of a water-soluble component and a water-insoluble component (sodium stearate/myristic acid and PEG/stearylalcohol) are able to induce a lag-time before release. However a perfect pulse-release is not obtained mainly because it is difficult to achieve a defect free coating with the hot melt coating technique. The release mechanism of these formulations is controlled by the mechanical failure of the coating.

This mechanism is strongly influenced by defects in the coating and therefore the deviation in the lag-time in individual pellets is large resulting in a rather poor pulse release behaviour.



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