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Evaluation of parameters involved in preparation and release of drug loaded in crosslinked matrices of alginate
Journal of Controlled Release 57 (1999) 223–232
Evaluation of parameters involved in preparation and release of drug loaded in crosslinked matrices of alginate a b a, S. Al-Musa , D. Abu Fara , A.A. Badwan * a
The Jordanian Pharmaceutical Manufacturing Co., PO. Box 94, 11710 Naor, Jordan b Chemical Engineering Department, University of Jordan, Amman 11942, Jordan Received 1 August 1997; accepted 31 May 1998
Abstract Parameters affecting the characteristics of the drug loaded crosslinked sodium alginate matrix films and the release of metoclopramide hydrochloride and cisapride from these matrices were studied. It was shown that the release rate is influenced by the crosslinking technique of the matrix film, crosslinker type and concentration, drug physico-chemical properties especially solubility and the molecular weight, acidity of the release medium, concentration and the loaded quantity of the drug in the matrix. The crosslinking process of the matrix film was shown to be an interfacial phenomenon and the nature of crosslinking depends on the crosslinker type and concentration. This work also showed that crosslinked alginate in a matrix form has limitation in practical use due to the effect of acidic medium on the crosslinking of the matrix film and hence, the rate of drug release. 1999 Elsevier Science B.V. All rights reserved. Keywords: Drug release; Controlled release; Polymer matrices; Sodium alginate; Film crosslinking
1. Introduction Some hydrophilic polymers have ion binding properties. Among these are alginate which belong to a family of unbranched binary copolymers of (1→ 4)-linked b-D-mannuronic acid and a-L-guluronic acid residues. The later may be present in various proportions altering the physico-chemical properties of the polymer formed [1]. Alginates show characteristic ion binding for multivalent cations and this forms the basis for their gelling properties. The alginate binding leads to the formation of covalent bonds leading to the perception of the insoluble *Corresponding author. Tel.: 1962-6-72720; fax: 1962-6727641; e-mail: [email protected]
hydrogel. Such crosslinking process stiffen and roughen the polymer and reduces the swelling in solvents. This generally leads to a reduction in the permeability of different solutes hindering the release of embodied drugs in alginate matrices, allowing these systems to be used in controlling the drug release [2]. The soluble sodium alginate was crosslinked with calcium chloride resulting in the formation of the insoluble calcium alginate. This system had been used successfully to delay the release of some drugs [2]. Different investigators reached a census that similar systems are only appropriately hinder the release of large molecular weight drugs while fail short to do so with smaller molecular weight compounds [3]. Badwan and Sharaiha [4] attempted to
0168-3659 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 98 )00096-0
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relate films permeability of calcium alginate and aluminum carboxymethylcellulose with the molecular weight of diffused drugs, crosslinker concentration and type and the morphological structure of the films. This study indicated that aluminum chloride was the most appropriate crosslinker for sodium carboxymethylcellulose, while calcium chloride was the most suitable crosslinker for sodium alginate films. The study also showed that the crosslinkers used were found to have an optimum operative concentration [4]. The texture as seen under the electron scanning microscope (ESM) of the crosslinked films of alginate and aluminum carboxymethylcellulose was a function of the crosslinker concentration. The increase in concentration showed a very distinct pattern which tends to be finer with the increase in concentration indicating more organized surfaces resulted from the maximum crosslinking of the surface. Such work draw the attention that study of the ion binding at defined surface thickness may lead to a better understanding of the mechanism controlling the release. Further, modifying the release from crosslinked calcium alginate or carboxymethylcellulose matrices by adding various additives such as starch, lactose, and gelatin was attempted and found to be a function of the modifier type and concentration [5]. Several investigators [6– 8] tried to use alginates as coated film appropriately crosslinked with cationic divalent ion. Rajaonvirony [6] prepared nano-particles from crosslinked alginate and proposed their utilization in drug targeting. Bhagat, et al [7] proposed a procedure to form a coating on solid dosage forms, termed ‘diffusioncontrolled interfacial complexation’. The process involved a chemical reaction between a reactant (calcium acetate) incorporated in the solid unit to be coated and a polymer solution (sodium alginate) forming the coating medium. They suggested that the rate of film formation is controlled by the rate of diffusion of calcium acetate through the reactant– polymer film. The procedure proposed by Bhagat, et al [7] was utilized by Iannucceli, et al [8] to coat carboxymethylcellulose beads crosslinked with aluminum chloride and loaded with ambroxol hydrochloride as a model drug by soaking in sodium alginate solution. The residual amount of the crosslinker induced an interfacial crosslinking reaction with the sodium alginate. They reported the forma-
tion of an insoluble, smooth and uniform in thickness coat around the beads. The morphological characteristics and the drug release process of the coated beads obtained by changing the coating time were evaluated. The above studies utilized the interfacial crosslinking where many parameters needed to be addressed. Consequently, the objective of the present work is to study the extent of ion binding in alginate films and parameters controlling the drug release from such films.
2. Materials and methods
2.1. Apparatus Apparatus used in the present work was a diffusion cell (Spectra / por Macrodialyzer 20041) supplied by Spectrum, 1100 Rankin road. Houston, Texas 77073-4716. The cell is made of transparent acrylic which enables the visualization of the film and solutions inside the cell. The cell capacity is 50 ml in each compartment. Each compartment has three sampling ports fitted with plugs. The cell is supplied with two snap clamps, and a stand.
2.2. Drug materials Two drugs differing in their physico-chemical properties were used. metoclopramide hydrochloride [C 14 H 22 ClN 3 O 2 .HCl.H 2 O] was used mainly because of its high solubility in water compared to the water insoluble cisapride monohydrate [C 23 H 29 ClFN 3 O 4 .H 2 O]. Both materials were obtained from The Jordanian Pharmaceutical Manufacturing Co. (JPM) and were of pharmaceutical quality.
2.3. Crosslinking materials Three metal salts were used as crosslinking materials: Calcium chloride dihydrate (Riedel de Haen analytical grade CaCl 2 .2H 2 O), Barium chloride dihydrate (Merck analytical grade BaCl 2 .2H 2 O), and Aluminum chloride hexahydrate (Merck analytical grade.AlCl 3 .6H 2 O).
S. Al-Musa et al. / Journal of Controlled Release 57 (1999) 223 – 232
2.4. Experimental procedure 2.4.1. Matrix film preparation A predefined amount (1.65 g) of sodium alginate was dissolved in 100 ml water, then a predefined amount of the drug material was added and stirred. Since metoclopramide hydrochloride is soluble in the system, the required amount was added directly to the solution after it was weighed accurately. Cisapride monohydrate is insoluble in the system, so it needed a special method for incorporation. A predefined quantity of cisapride monohydrate was dissolved in a minimal amount of dichloromethane and added to the alginate solution and stirred until all the dichloromethane was evaporated, a heating temperature of 558C was used initially to facilitate the evaporation. After the solutions or suspensions were ready, pre-defined accurately weighed amounts were poured in 9 cm diameter glass petridishes and were dried in an oven at 558C. 2.4.2. Crosslinking of matrix films The following five crosslinking procedures were used depending on the method of addition of the crosslinking solution. It has been found that the
225
crosslinking reaction is fast and the time of crosslinking has no effect after 30 min [9]. Regular cross-linking: 25 ml of the prepared CaCl 2 solution with known concentration were poured into a petridish containing the prepared matrix film. The film was left under cross-linking solution for 1 h, then the solution was discarded and the film was used immediately. Inverted film cross-linking: The prepared matrix film was taken out of the petridish, and inverted so as the lower surface becomes the upper, and the same procedure described above was used. Combined cross-linking: 25 ml of the prepared solution with known concentration were poured into a petridish containing the prepared matrix film, the film was left for 30 min, then was inverted inside the dish so that the lower surface becomes the upper, and was left for another 30 min, the solution was then discarded and the film was immediately used. Lower surface cross-linking: A 9 cm diameter perforated plastic plate was fitted to a petridish. A quantity of the known cross-linking solution was added until a layer of the solution covered the surface of the perforated plate. The prepared matrix film was then placed on the plate so as only the lower surface of the film was in contact with the
Table 1 Experimental Parameters and Conditions Parameter studied
Drug used
Crosslinker
Crosslinking procedure
Release media
Crosslinking procedure – – – – – Crosslinker type – – – – – Drug solubility and hydrophobicity – – – Release media – – –
Metoclopramide hydrochloride – – – – Cisapride Metoclopramide hydrochloride – – – – – Metoclopramide hydrochloride – Cisapride – Metoclopramide – – –
30% CaCl 2 solution – – – – – 30% CaCl 2 solution – 30% BaCl 2 solution 30% AlCl 3 solution – 30% SnCl 4 solution 30% CaCl 2 solution – – – 30% CaCl 2 solution – – –
Regular Inverted Regular Combined Upper and lower surface – Lower surface Upper surface Lower surface – Upper surface Lower surface Lower surface – – – Lower surface – Upper surface –
Water – – – – 0.1N Methanolic HCl Water – – – – – 0.1 NHCl Water Water 0.1N Methanolic HCl Water 0.1N HCl Water 0.1N HCl
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cross-linking solution. The film was left for 30 min and then was taken out of the solution. Upper surface cross-linking: The same procedure for lower surface cross-linking was followed, except that the exposed surface to the cross-linking solution is the upper surface of the film.
2.4.3. Release of drugs from crosslinked matrix films: The release of drug materials from crosslinked sodium alginate matrix films was studied by installing the matrix film between the two cell compartments and filling both compartments with the proper release medium for the drug. Samples from each compartment were withdrawn at different periods of time, the withdrawn samples were compensated immediately by the same volume of pure release medium. The samples were diluted and assayed using spectrophotometer at the proper wave length. This procedure was continued until a constant concentration was obtained in each compartment. Every release experiment was repeated three times. The experimental runs, studied parameters, and experimental conditions are summarized in Table 1.
3. Results and discussion The release of metoclopramide hydrochloride from matrix films crosslinked with calcium chloride and using different crosslinking procedures is shown in Fig. 1. Both regular and inverted crosslinking procedures (Fig. 1a) show that there is a lower drug quantity released from the film surface which was directly exposed to the crosslinking solution. To further investigate such observation, lower surface crosslinking and upper surface crosslinking procedures were carried out separately. Thicker films were guard against that the crosslinker solution is not penetrated to the other surface. As anticipated, it is clearly illustrated (Fig. 1b) that the crosslinking is very much enhanced at the surface directly exposed to the crosslinking solution and thus reduces the release from that surface. The above expectation was in the light of the observation that the crosslinked film, when placed in water, started to dissolve at the surface which was not exposed to the crosslinker solution. In addition, some parts of the films are
Fig. 1. Release of metoclopmaride hydrochloride using 30% CaCl 2 solution as crosslinker; (a) regular and inverted crosslinking procedures, (b) lower surface and upper surface crosslinking procedures.
shown to be swollen. Swelling was indicated by the gel formation in the film which looks like a nylon bag that contains gel as shown in Fig. 2. It appears that pockets of gel formation take place in the close vicinity of other sites than gel junction. On the other hand, a film which was exposed to the crosslinker solution from both surfaces was found to be completely insoluble and maintain its stability. This observation indicates that the crosslinking process is terminated before the crosslinking ions can travel from one surface of the film to the other. Thus, it is believed that crosslinking starts at the exposed surface yielding an almost complete crosslinked surface resulting in a decreased voids size and number. Consequently, there will be lower chances for the remaining crosslinker to diffuse further in the body of the film. Moreover, the quantity of crosslinker that succeeded to penetrate the surface and
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Fig. 2. The upper surface of sodium alginate film crosslinked by calcium chloride solution using lower surface crosslinking procedure.
crosslink an additional number of sites in the adjacent layers leads to further hindrance of the ionic movement. This procedure continues until no further penetration is possible which leads to the completion of the crosslinking process without crosslinking the remaining layers. Fig. 3 shows the release patterns of metoclopramide hydrochloride using aluminum, calcium, and barium chlorides as crosslinkers and applying lower surface crosslinking procedure. It is seen that the difference in release from the surface which was directly exposed to the crosslinker and the other surface of the film is very much reduced in case of
crosslinking with AlCl 3 solution. The explanation of this observation could be related to the mechanism of the bonding of calcium, barium, and aluminum cations to alginate anions. Since calcium and barium cation are divalent, its bonding to alginate is expected to occur in a planar two dimensional manner as represented in the egg box model illustrated in Fig. 4 [10]. On the other hand, trivalent aluminium cation, as also shown in Fig. 4, is expected to form a three dimensional valent bonding structure with the alginate. This three dimensional bonding model is expected to be the reason for the extended crosslinking through the whole body of the film. This is
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Fig. 3. Release of metoclopramide hydrochloride using three different crosslinkers and applying lower surface crosslinking procedure.
Fig. 4. Expected mechanism of reaction between calcium and aluminum cations and sodium alginate matrices.
because crosslinking occurs in two different planes of the film at the same time resulting in compacting the alginate molecules. Furthermore the small size of the aluminium cation (0.58A) [11] is expected to facilitate its diffusion through the body of the film, which may occur before crosslinking on the surface takes place and hinders the cation mobility into the film. This is illustrated in Fig. 5 which shows scanning electron microscope pictures of films crosslinked with barium, calcium, and aluminium chlorides. It is clearly shown (Fig. 5a) that a large number of barium ions are just attached to outer surface of the film and were not able to penetrate it. This occurred to a much smaller number of calcium ions (Fig. 5b). On the other hand, it is obvious that almost all the aluminum ions were able to diffuse into the film before complete crosslinking of the surface occurred (Fig. 5c). Thus it can be concluded that crosslinking of the alginate film with barium and, to a less extent, with calcium ions is a diffusion controlled process. It is also shown that the total release from film crosslinked with AlCl 3 solution is lower than the total release from the other two films crosslinked by CaCl 2 and BaCl 2 solutions. This is attributed to the tight film structure that entraps the drug molecules and hinders their mobility. The divalent salts CaCl 2 and BaCl 2 are expected to crosslink the alginate film in a similar mechanism. But it was observed that calcium chloride produced films that posses a smaller difference in release between the two surfaces than was shown by films crosslinked with barium chloride as Fig. 3 shows. This could be explained by noting that the degree of crosslinking depends on the ability of the crosslinker ions to diffuse through the film. This diffusion ability is a function of the ionic size. Since the barium ion ˚ compared to 0.97 A ˚ for has a radius of 1.35 A calcium ion [11], barium ions are expected to fill a larger space between the alginate molecules producing a tight arrangement at the surface with smaller voids as illustrated in Fig. 6. Hence, the passage of large barium ions through the surface is hindered, resulting in limited crosslinking through the film, and this explains the negligible release from the lower surface and the fast and much higher release from the other surface of the film as clearly shown in Fig. 3. On the other hand, the smaller size of calcium
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229
Fig. 5. Scanning electron microscope pictures of films crosslinked within (a) barium chloride, (b) calcium chloride and (c) aluminum chloride.
Fig. 6. Egg-box model representing calcium and barium cations reacting with alginates.
cations compared to barium cations is responsible for the less tight structure on the surface which allows the ions to diffuse to a certain depth and crosslink some additional sites resulting in closer release patterns between the two surfaces. Fig. 7a shows the release of metoclopramide hydrochloride and cisapride from a matrix film prepared by the lower surface crosslinking procedure. It is observed that metoclopramide hydrochloride, which is freely soluble in the sodium alginate solution, is shown to be released at approximately similar rate from the two surfaces with the effect of crosslinking appearing more at the lower surface of the film as expected.
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Fig. 7. Effect of solubility and hydrophobicity on drug release using lower surface crosslinking procedure. (a) cisparide versus metochlopramide hydrochloride, (b) 5 mg versus 25 mg concentration of cisapride in the film.
Contrary to the expected, it is clearly shown that the release of cisapride from the lower surface of the matrix film is much higher than that from the upper surface. This release phenomena of cisapride was crosschecked by varying the drug loading in the matrix. Fig. 7b shows the large difference in release between upper and lower surfaces of the matrix is appreciably reduced by lowering the drug loading. The above result was proved using various drug loadings. Thus the high release of cisapride from the lower surface of the film is believed to be due to a non-homogenous distribution of cisapride across the thickness of the film in spite of the fairly homogenous mixture of sodium alginate solution and cisapride as assured by the preparation procedure. Since cisapride is insoluble in water and hydrophobic, its hydrophobicity and density enable the molecules to escape from water and concentrate towards the glass surface of the
petridish and thus always accumulate at the lower surface of the film. This phenomenon is clearly illustrated in Fig. 8 which shows the morphology of the upper and lower surfaces of a cisapride-loaded film. It appears that the lower surface has a smoother structure which is believed to be caused by the sedimentation of the fine particles of cisapride at the lower surface of the film. The smoothness of the lower surface of the film is expected to increase by increasing the concentration of cisapride in the film. This is clearly illustrated in part C of Fig. 8, which represents the lower surface of a film loaded with a larger amount of cisapride. The three dimensional part of the pictures also supports the above argument. Water and 0.1 N HCl solution were used to study the effect of the release media on the release of drug from crosslinked sodium alginate matrix films. Fig. 9 depicts the results using lower surface crosslinking procedure. The difference in release between the upper and lower surfaces of the film was very much reduced when 0.1 N HCl solution was used as a release medium instead of water. This may be attributed to the conversion of calcium alginates and sodium alginates in the crosslinked film into alginic acid as a result of the reaction between the alginate and HCl [12]. The conversion into alginic acid results in lowering the degree of crosslinking by converting the alginate salt into alginic acid and therefore decreasing the film ability to hinder the drug movement. The same results were obtained using upper surface crosslinking procedure. This is an emphasis that crosslinking process is not completed throughout the film thickness leading to an interfacial nature of the crosslinking. Fig. 10 shows the release of cisapride from matrix films prepared by lower surface and upper surface crosslinking procedures separately and using 0.1 N HCl as a release medium. It is shown that, regardless of the crosslinking procedure and the release media, the release of cisapride from the lower surface of the film is always higher. Since 0.1 N HCl was used as a release medium, it is expected that the calcium alginate in the crosslinked side and the sodium alginate in the other side were both converted to alginic acid. This results in a homogeneous alginic acid film. Accordingly, the distribution of cisapride in the matrix is now the limiting factor for its
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Fig. 8. Scanning electron microscope pictures of sodium alginate films loaded with cisapride (a) upper surface 10mg / film, (b) lower surface 10mg / film, and (c) lower surface 25 mg / film.
Fig. 9. Effect of media acidity on the release of metoclopramide hydrochloride using lower surface crosslinking procedure.
Fig. 10. Effect of crosslinking procedure on release of cisapride.
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release. As was discussed earlier and illustrated in Fig. 8, the concentration of cisapride in the lower part of the film due to its hydrophobicity and density is the reason for the release of higher quantities of the drug from that surface in both cases.
4. Conclusions It has been shown that the crosslinking of the matrix film is an interfacial phenomenon and the crosslinker cations can only migrate to a limited distance from the surface. Thus, the crosslinking technique plays an important role in defining the film surface morphology and consequently its diffusion properties. The crosslinker type is shown to have a pronounce influence on the drug release. The nature of binding and the extent of cation transferring from one end to another is a function of size, hydration and valence of the cations used. In addition the release from the matrices indicated that solubility and the size of the molecules have a major role in the release phenomena. The release medium has a dramatic influence on the alginate membrane. The HCl medium reacts with the alginate resulting in alginic acid formation. This formation is random and may take place at the surface of the film. It can be concluded that the above reaction would hamper the use of crosslinked alginates in practical systems where they are by nature to be exposed to the acidic medium in the stomach. Such limitation of this system would definitely lower to a great extent the use of alginates on their own as monolithic devices in controlled release systems.
References [1] S.T. Moe, K.I. Draget, G.S. Break, O. Smidsrod, Alginates, in A.M. Stephen (Ed.), Food polysaccharides and their applications, first ed., Marcel Dekker, New York, 1995, pp. 245–286. [2] A. Badwan, A. Abumalooh, E. Sallam, A. Abukalaf, O. Jawan, A sustained release drug delivery system using calcium alginate beads, Drug Dev. Indus. Pharm. 11 (1983) 239–256. [3] G.S. Kwon, Y.H. Bae, H. Cremers, J. Feijen, S.W. Kim, Release of macromolecules from albumin-heparin microspheres, Int. J. Pharm. 79 (1992) 191–198. [4] A. Badwan, D. Sharaiha, Permeability studies of some hydrophilic polymeric films, Fourth International Conference on Pharmaceutical Technology, Paris, vol. IV, 1987, pp. 131–139. [5] A.A. Badwan, A. Abu Malouh, Production and properties of crosslinked sodium carboxymethylcellulose granules used in controlled release preparations, Fourth International Conference on Pharmaceutical Technology, Paris, vol. III, 1987, pp. 126–135. [6] M. Rajaonarivony, C. Vauthier, G. Covarraze, F. Puisieux, P. Couveur, Development of a new drug carrier made from alginate, J. Pharm. Sci. 82(9) (1993) 912–917. [7] H.R. Bhagat, R.W. Mendes, E. Mathiouz, H.N. Bharagava, A novel, self correcting membrane coating technique, Pharm. Res. 8(5) (1991) 576–583. [8] V. Iannuccelli, G. Coppi, M.A. Vandelli, E. Leo, M.T. Bernabei, Bead coating process via an excess of crosslinking agent, Drug Dev. Ind. Pharm. 21(20) (1995) 2307– 2322. [9] S.N. Al-Musa, Drug release from some hydrophilic polymer matrices, M.Sc. Thesis, University of Jordan, Amman, Jordan 1996. [10] G.T. Grant, E.R. Morris, D.A. Rees, P.J. Smith, D. Thom, Biological interaction between polysacarides and divalent cations: The egg-box model, FEBS Lett. 32(1) (1973) 195. [11] J. Burgess, Metal Ions in Solution, first ed., Ellis Horwood, England, 1978, pp. 137–195. [12] S.T. Moe, K.I. Draget, G.S. Break, O. Smidsrod, Alginates, in: A.M. Stephen (Ed.), Food Polysacharides and Their Applications, 1st Ed, Marcel Dekker, New York, 1995, pp. 245–286.
Evaluation of parameters involved in preparation and release of drug loaded in crosslinked matrices of alginate a b a, S. Al-Musa , D. Abu Fara , A.A. Badwan * a
The Jordanian Pharmaceutical Manufacturing Co., PO. Box 94, 11710 Naor, Jordan b Chemical Engineering Department, University of Jordan, Amman 11942, Jordan Received 1 August 1997; accepted 31 May 1998
Abstract Parameters affecting the characteristics of the drug loaded crosslinked sodium alginate matrix films and the release of metoclopramide hydrochloride and cisapride from these matrices were studied. It was shown that the release rate is influenced by the crosslinking technique of the matrix film, crosslinker type and concentration, drug physico-chemical properties especially solubility and the molecular weight, acidity of the release medium, concentration and the loaded quantity of the drug in the matrix. The crosslinking process of the matrix film was shown to be an interfacial phenomenon and the nature of crosslinking depends on the crosslinker type and concentration. This work also showed that crosslinked alginate in a matrix form has limitation in practical use due to the effect of acidic medium on the crosslinking of the matrix film and hence, the rate of drug release. 1999 Elsevier Science B.V. All rights reserved. Keywords: Drug release; Controlled release; Polymer matrices; Sodium alginate; Film crosslinking
1. Introduction Some hydrophilic polymers have ion binding properties. Among these are alginate which belong to a family of unbranched binary copolymers of (1→ 4)-linked b-D-mannuronic acid and a-L-guluronic acid residues. The later may be present in various proportions altering the physico-chemical properties of the polymer formed [1]. Alginates show characteristic ion binding for multivalent cations and this forms the basis for their gelling properties. The alginate binding leads to the formation of covalent bonds leading to the perception of the insoluble *Corresponding author. Tel.: 1962-6-72720; fax: 1962-6727641; e-mail: [email protected]
hydrogel. Such crosslinking process stiffen and roughen the polymer and reduces the swelling in solvents. This generally leads to a reduction in the permeability of different solutes hindering the release of embodied drugs in alginate matrices, allowing these systems to be used in controlling the drug release [2]. The soluble sodium alginate was crosslinked with calcium chloride resulting in the formation of the insoluble calcium alginate. This system had been used successfully to delay the release of some drugs [2]. Different investigators reached a census that similar systems are only appropriately hinder the release of large molecular weight drugs while fail short to do so with smaller molecular weight compounds [3]. Badwan and Sharaiha [4] attempted to
0168-3659 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 98 )00096-0
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relate films permeability of calcium alginate and aluminum carboxymethylcellulose with the molecular weight of diffused drugs, crosslinker concentration and type and the morphological structure of the films. This study indicated that aluminum chloride was the most appropriate crosslinker for sodium carboxymethylcellulose, while calcium chloride was the most suitable crosslinker for sodium alginate films. The study also showed that the crosslinkers used were found to have an optimum operative concentration [4]. The texture as seen under the electron scanning microscope (ESM) of the crosslinked films of alginate and aluminum carboxymethylcellulose was a function of the crosslinker concentration. The increase in concentration showed a very distinct pattern which tends to be finer with the increase in concentration indicating more organized surfaces resulted from the maximum crosslinking of the surface. Such work draw the attention that study of the ion binding at defined surface thickness may lead to a better understanding of the mechanism controlling the release. Further, modifying the release from crosslinked calcium alginate or carboxymethylcellulose matrices by adding various additives such as starch, lactose, and gelatin was attempted and found to be a function of the modifier type and concentration [5]. Several investigators [6– 8] tried to use alginates as coated film appropriately crosslinked with cationic divalent ion. Rajaonvirony [6] prepared nano-particles from crosslinked alginate and proposed their utilization in drug targeting. Bhagat, et al [7] proposed a procedure to form a coating on solid dosage forms, termed ‘diffusioncontrolled interfacial complexation’. The process involved a chemical reaction between a reactant (calcium acetate) incorporated in the solid unit to be coated and a polymer solution (sodium alginate) forming the coating medium. They suggested that the rate of film formation is controlled by the rate of diffusion of calcium acetate through the reactant– polymer film. The procedure proposed by Bhagat, et al [7] was utilized by Iannucceli, et al [8] to coat carboxymethylcellulose beads crosslinked with aluminum chloride and loaded with ambroxol hydrochloride as a model drug by soaking in sodium alginate solution. The residual amount of the crosslinker induced an interfacial crosslinking reaction with the sodium alginate. They reported the forma-
tion of an insoluble, smooth and uniform in thickness coat around the beads. The morphological characteristics and the drug release process of the coated beads obtained by changing the coating time were evaluated. The above studies utilized the interfacial crosslinking where many parameters needed to be addressed. Consequently, the objective of the present work is to study the extent of ion binding in alginate films and parameters controlling the drug release from such films.
2. Materials and methods
2.1. Apparatus Apparatus used in the present work was a diffusion cell (Spectra / por Macrodialyzer 20041) supplied by Spectrum, 1100 Rankin road. Houston, Texas 77073-4716. The cell is made of transparent acrylic which enables the visualization of the film and solutions inside the cell. The cell capacity is 50 ml in each compartment. Each compartment has three sampling ports fitted with plugs. The cell is supplied with two snap clamps, and a stand.
2.2. Drug materials Two drugs differing in their physico-chemical properties were used. metoclopramide hydrochloride [C 14 H 22 ClN 3 O 2 .HCl.H 2 O] was used mainly because of its high solubility in water compared to the water insoluble cisapride monohydrate [C 23 H 29 ClFN 3 O 4 .H 2 O]. Both materials were obtained from The Jordanian Pharmaceutical Manufacturing Co. (JPM) and were of pharmaceutical quality.
2.3. Crosslinking materials Three metal salts were used as crosslinking materials: Calcium chloride dihydrate (Riedel de Haen analytical grade CaCl 2 .2H 2 O), Barium chloride dihydrate (Merck analytical grade BaCl 2 .2H 2 O), and Aluminum chloride hexahydrate (Merck analytical grade.AlCl 3 .6H 2 O).
S. Al-Musa et al. / Journal of Controlled Release 57 (1999) 223 – 232
2.4. Experimental procedure 2.4.1. Matrix film preparation A predefined amount (1.65 g) of sodium alginate was dissolved in 100 ml water, then a predefined amount of the drug material was added and stirred. Since metoclopramide hydrochloride is soluble in the system, the required amount was added directly to the solution after it was weighed accurately. Cisapride monohydrate is insoluble in the system, so it needed a special method for incorporation. A predefined quantity of cisapride monohydrate was dissolved in a minimal amount of dichloromethane and added to the alginate solution and stirred until all the dichloromethane was evaporated, a heating temperature of 558C was used initially to facilitate the evaporation. After the solutions or suspensions were ready, pre-defined accurately weighed amounts were poured in 9 cm diameter glass petridishes and were dried in an oven at 558C. 2.4.2. Crosslinking of matrix films The following five crosslinking procedures were used depending on the method of addition of the crosslinking solution. It has been found that the
225
crosslinking reaction is fast and the time of crosslinking has no effect after 30 min [9]. Regular cross-linking: 25 ml of the prepared CaCl 2 solution with known concentration were poured into a petridish containing the prepared matrix film. The film was left under cross-linking solution for 1 h, then the solution was discarded and the film was used immediately. Inverted film cross-linking: The prepared matrix film was taken out of the petridish, and inverted so as the lower surface becomes the upper, and the same procedure described above was used. Combined cross-linking: 25 ml of the prepared solution with known concentration were poured into a petridish containing the prepared matrix film, the film was left for 30 min, then was inverted inside the dish so that the lower surface becomes the upper, and was left for another 30 min, the solution was then discarded and the film was immediately used. Lower surface cross-linking: A 9 cm diameter perforated plastic plate was fitted to a petridish. A quantity of the known cross-linking solution was added until a layer of the solution covered the surface of the perforated plate. The prepared matrix film was then placed on the plate so as only the lower surface of the film was in contact with the
Table 1 Experimental Parameters and Conditions Parameter studied
Drug used
Crosslinker
Crosslinking procedure
Release media
Crosslinking procedure – – – – – Crosslinker type – – – – – Drug solubility and hydrophobicity – – – Release media – – –
Metoclopramide hydrochloride – – – – Cisapride Metoclopramide hydrochloride – – – – – Metoclopramide hydrochloride – Cisapride – Metoclopramide – – –
30% CaCl 2 solution – – – – – 30% CaCl 2 solution – 30% BaCl 2 solution 30% AlCl 3 solution – 30% SnCl 4 solution 30% CaCl 2 solution – – – 30% CaCl 2 solution – – –
Regular Inverted Regular Combined Upper and lower surface – Lower surface Upper surface Lower surface – Upper surface Lower surface Lower surface – – – Lower surface – Upper surface –
Water – – – – 0.1N Methanolic HCl Water – – – – – 0.1 NHCl Water Water 0.1N Methanolic HCl Water 0.1N HCl Water 0.1N HCl
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cross-linking solution. The film was left for 30 min and then was taken out of the solution. Upper surface cross-linking: The same procedure for lower surface cross-linking was followed, except that the exposed surface to the cross-linking solution is the upper surface of the film.
2.4.3. Release of drugs from crosslinked matrix films: The release of drug materials from crosslinked sodium alginate matrix films was studied by installing the matrix film between the two cell compartments and filling both compartments with the proper release medium for the drug. Samples from each compartment were withdrawn at different periods of time, the withdrawn samples were compensated immediately by the same volume of pure release medium. The samples were diluted and assayed using spectrophotometer at the proper wave length. This procedure was continued until a constant concentration was obtained in each compartment. Every release experiment was repeated three times. The experimental runs, studied parameters, and experimental conditions are summarized in Table 1.
3. Results and discussion The release of metoclopramide hydrochloride from matrix films crosslinked with calcium chloride and using different crosslinking procedures is shown in Fig. 1. Both regular and inverted crosslinking procedures (Fig. 1a) show that there is a lower drug quantity released from the film surface which was directly exposed to the crosslinking solution. To further investigate such observation, lower surface crosslinking and upper surface crosslinking procedures were carried out separately. Thicker films were guard against that the crosslinker solution is not penetrated to the other surface. As anticipated, it is clearly illustrated (Fig. 1b) that the crosslinking is very much enhanced at the surface directly exposed to the crosslinking solution and thus reduces the release from that surface. The above expectation was in the light of the observation that the crosslinked film, when placed in water, started to dissolve at the surface which was not exposed to the crosslinker solution. In addition, some parts of the films are
Fig. 1. Release of metoclopmaride hydrochloride using 30% CaCl 2 solution as crosslinker; (a) regular and inverted crosslinking procedures, (b) lower surface and upper surface crosslinking procedures.
shown to be swollen. Swelling was indicated by the gel formation in the film which looks like a nylon bag that contains gel as shown in Fig. 2. It appears that pockets of gel formation take place in the close vicinity of other sites than gel junction. On the other hand, a film which was exposed to the crosslinker solution from both surfaces was found to be completely insoluble and maintain its stability. This observation indicates that the crosslinking process is terminated before the crosslinking ions can travel from one surface of the film to the other. Thus, it is believed that crosslinking starts at the exposed surface yielding an almost complete crosslinked surface resulting in a decreased voids size and number. Consequently, there will be lower chances for the remaining crosslinker to diffuse further in the body of the film. Moreover, the quantity of crosslinker that succeeded to penetrate the surface and
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Fig. 2. The upper surface of sodium alginate film crosslinked by calcium chloride solution using lower surface crosslinking procedure.
crosslink an additional number of sites in the adjacent layers leads to further hindrance of the ionic movement. This procedure continues until no further penetration is possible which leads to the completion of the crosslinking process without crosslinking the remaining layers. Fig. 3 shows the release patterns of metoclopramide hydrochloride using aluminum, calcium, and barium chlorides as crosslinkers and applying lower surface crosslinking procedure. It is seen that the difference in release from the surface which was directly exposed to the crosslinker and the other surface of the film is very much reduced in case of
crosslinking with AlCl 3 solution. The explanation of this observation could be related to the mechanism of the bonding of calcium, barium, and aluminum cations to alginate anions. Since calcium and barium cation are divalent, its bonding to alginate is expected to occur in a planar two dimensional manner as represented in the egg box model illustrated in Fig. 4 [10]. On the other hand, trivalent aluminium cation, as also shown in Fig. 4, is expected to form a three dimensional valent bonding structure with the alginate. This three dimensional bonding model is expected to be the reason for the extended crosslinking through the whole body of the film. This is
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Fig. 3. Release of metoclopramide hydrochloride using three different crosslinkers and applying lower surface crosslinking procedure.
Fig. 4. Expected mechanism of reaction between calcium and aluminum cations and sodium alginate matrices.
because crosslinking occurs in two different planes of the film at the same time resulting in compacting the alginate molecules. Furthermore the small size of the aluminium cation (0.58A) [11] is expected to facilitate its diffusion through the body of the film, which may occur before crosslinking on the surface takes place and hinders the cation mobility into the film. This is illustrated in Fig. 5 which shows scanning electron microscope pictures of films crosslinked with barium, calcium, and aluminium chlorides. It is clearly shown (Fig. 5a) that a large number of barium ions are just attached to outer surface of the film and were not able to penetrate it. This occurred to a much smaller number of calcium ions (Fig. 5b). On the other hand, it is obvious that almost all the aluminum ions were able to diffuse into the film before complete crosslinking of the surface occurred (Fig. 5c). Thus it can be concluded that crosslinking of the alginate film with barium and, to a less extent, with calcium ions is a diffusion controlled process. It is also shown that the total release from film crosslinked with AlCl 3 solution is lower than the total release from the other two films crosslinked by CaCl 2 and BaCl 2 solutions. This is attributed to the tight film structure that entraps the drug molecules and hinders their mobility. The divalent salts CaCl 2 and BaCl 2 are expected to crosslink the alginate film in a similar mechanism. But it was observed that calcium chloride produced films that posses a smaller difference in release between the two surfaces than was shown by films crosslinked with barium chloride as Fig. 3 shows. This could be explained by noting that the degree of crosslinking depends on the ability of the crosslinker ions to diffuse through the film. This diffusion ability is a function of the ionic size. Since the barium ion ˚ compared to 0.97 A ˚ for has a radius of 1.35 A calcium ion [11], barium ions are expected to fill a larger space between the alginate molecules producing a tight arrangement at the surface with smaller voids as illustrated in Fig. 6. Hence, the passage of large barium ions through the surface is hindered, resulting in limited crosslinking through the film, and this explains the negligible release from the lower surface and the fast and much higher release from the other surface of the film as clearly shown in Fig. 3. On the other hand, the smaller size of calcium
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Fig. 5. Scanning electron microscope pictures of films crosslinked within (a) barium chloride, (b) calcium chloride and (c) aluminum chloride.
Fig. 6. Egg-box model representing calcium and barium cations reacting with alginates.
cations compared to barium cations is responsible for the less tight structure on the surface which allows the ions to diffuse to a certain depth and crosslink some additional sites resulting in closer release patterns between the two surfaces. Fig. 7a shows the release of metoclopramide hydrochloride and cisapride from a matrix film prepared by the lower surface crosslinking procedure. It is observed that metoclopramide hydrochloride, which is freely soluble in the sodium alginate solution, is shown to be released at approximately similar rate from the two surfaces with the effect of crosslinking appearing more at the lower surface of the film as expected.
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Fig. 7. Effect of solubility and hydrophobicity on drug release using lower surface crosslinking procedure. (a) cisparide versus metochlopramide hydrochloride, (b) 5 mg versus 25 mg concentration of cisapride in the film.
Contrary to the expected, it is clearly shown that the release of cisapride from the lower surface of the matrix film is much higher than that from the upper surface. This release phenomena of cisapride was crosschecked by varying the drug loading in the matrix. Fig. 7b shows the large difference in release between upper and lower surfaces of the matrix is appreciably reduced by lowering the drug loading. The above result was proved using various drug loadings. Thus the high release of cisapride from the lower surface of the film is believed to be due to a non-homogenous distribution of cisapride across the thickness of the film in spite of the fairly homogenous mixture of sodium alginate solution and cisapride as assured by the preparation procedure. Since cisapride is insoluble in water and hydrophobic, its hydrophobicity and density enable the molecules to escape from water and concentrate towards the glass surface of the
petridish and thus always accumulate at the lower surface of the film. This phenomenon is clearly illustrated in Fig. 8 which shows the morphology of the upper and lower surfaces of a cisapride-loaded film. It appears that the lower surface has a smoother structure which is believed to be caused by the sedimentation of the fine particles of cisapride at the lower surface of the film. The smoothness of the lower surface of the film is expected to increase by increasing the concentration of cisapride in the film. This is clearly illustrated in part C of Fig. 8, which represents the lower surface of a film loaded with a larger amount of cisapride. The three dimensional part of the pictures also supports the above argument. Water and 0.1 N HCl solution were used to study the effect of the release media on the release of drug from crosslinked sodium alginate matrix films. Fig. 9 depicts the results using lower surface crosslinking procedure. The difference in release between the upper and lower surfaces of the film was very much reduced when 0.1 N HCl solution was used as a release medium instead of water. This may be attributed to the conversion of calcium alginates and sodium alginates in the crosslinked film into alginic acid as a result of the reaction between the alginate and HCl [12]. The conversion into alginic acid results in lowering the degree of crosslinking by converting the alginate salt into alginic acid and therefore decreasing the film ability to hinder the drug movement. The same results were obtained using upper surface crosslinking procedure. This is an emphasis that crosslinking process is not completed throughout the film thickness leading to an interfacial nature of the crosslinking. Fig. 10 shows the release of cisapride from matrix films prepared by lower surface and upper surface crosslinking procedures separately and using 0.1 N HCl as a release medium. It is shown that, regardless of the crosslinking procedure and the release media, the release of cisapride from the lower surface of the film is always higher. Since 0.1 N HCl was used as a release medium, it is expected that the calcium alginate in the crosslinked side and the sodium alginate in the other side were both converted to alginic acid. This results in a homogeneous alginic acid film. Accordingly, the distribution of cisapride in the matrix is now the limiting factor for its
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Fig. 8. Scanning electron microscope pictures of sodium alginate films loaded with cisapride (a) upper surface 10mg / film, (b) lower surface 10mg / film, and (c) lower surface 25 mg / film.
Fig. 9. Effect of media acidity on the release of metoclopramide hydrochloride using lower surface crosslinking procedure.
Fig. 10. Effect of crosslinking procedure on release of cisapride.
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release. As was discussed earlier and illustrated in Fig. 8, the concentration of cisapride in the lower part of the film due to its hydrophobicity and density is the reason for the release of higher quantities of the drug from that surface in both cases.
4. Conclusions It has been shown that the crosslinking of the matrix film is an interfacial phenomenon and the crosslinker cations can only migrate to a limited distance from the surface. Thus, the crosslinking technique plays an important role in defining the film surface morphology and consequently its diffusion properties. The crosslinker type is shown to have a pronounce influence on the drug release. The nature of binding and the extent of cation transferring from one end to another is a function of size, hydration and valence of the cations used. In addition the release from the matrices indicated that solubility and the size of the molecules have a major role in the release phenomena. The release medium has a dramatic influence on the alginate membrane. The HCl medium reacts with the alginate resulting in alginic acid formation. This formation is random and may take place at the surface of the film. It can be concluded that the above reaction would hamper the use of crosslinked alginates in practical systems where they are by nature to be exposed to the acidic medium in the stomach. Such limitation of this system would definitely lower to a great extent the use of alginates on their own as monolithic devices in controlled release systems.
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