Effect of Surfactants on the Release of Griseofulvin from

Chapter 17

Effect of Surfactants on the Release of Griseofulvin from Polyvinylpyrrolidone Dispersions 1

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 16, 2015 | http://pubs.acs.org Publication Date: September 24, 1998 | doi: 10.1021/bk-1998-0709.ch017

Hanife Akin, Jeorge Heller , and Frank W. Harris The Maurice Moron Institute and Department of Polymer Science, The University of Akron, Akron, OH 44325-3909 The overall objective of this work was to increase the apparent water-solubility and dissolution rate of the water-insoluble drug griseofulvin (gris) so as to enhance its bioavailability, absorption and therapeutic efficacy. This was to be accomplished by incorporating the drug in polyvinyl pyrrolidone (PVP) solid dispersions. Thus, gris and PVP were dissolved in a common solvent and then isolated as an intimate mixture or complex. In this work, the effect of several surfactants on the dissolution rates of gris from the gris/PVP solid dispersions was determined. The anionic surfactant sodium dodecyl sulfate (SDS), the cationic surfactant deodecyltrimethylammonium bromide (DTAB) and the non -ionic surfactant polyoxyethylene dodecylether (Brij-35) were added in equivalent amounts (0.01% w/v) to the release media. The anionic surfactant greatly enhanced the dissolution rate of gris. The non-ionic and cationic surfactants showed a less pronounced positive influence on the release of gris.

Drugs with low water solubilities are often characterized by low absorption and poor oral bioavailability. Thus, many studies have been carried out aimed at increasing the dissolution rates and solubilities of such drugs to increase their total bioavailability in gastrointestinal (GI) absorption. For example, hydrophobic drugs have been dispersed in water-soluble polymers to form so-called "solid dispersions"(7). A solid dispersion is a multi-particulate delivery system that consists of one or more active ingredients dispersed in an inert carrier or matrix. The use of solid dispersions to increase the rate of dissolution of drug was first demonstrated by Sekiguchi and Obi (2). The enhanced dissolution rates observed from many of these formulations has been attributed to several different factors including : a) the existence of a metastable form of the drug that can be stabilized by specific interactions with the 'Current address: Advanced Polymer Systems, 3696 Haven Avenue, Redwood City, C A 94063.

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©1998 American Chemical Society

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polymer, such as, hydrogen bonds (3,4); b) a reduction in particle size or particle agglomeration due to the presence of the polymer (5-7)\ c) an increase in the surface wetting of the drug; and d) the formation of water-soluble drug/polymer complexes (8). The physical forms of the drug and the dispersions produced depends on factors such as: a) the method of preparation, b) the solvent used c) the molecular weight of the polymer d) the drug loading, and e) the physico-chemical properties of the drug. Drug-carrier interactions must be carefully evaluated during preformulation studies, since they can significantly affect the system's biopharmaceutical properties. Therefore, a through understanding of these interactions is necessary to formulate an effective solid dispersion dosage form or particular drug. In the solid dispersion technology, an ideal carrier should meet the following criteria: - it should be freely water soluble with intrinsic rapid dissolution properties; - it should be non-toxic; - it should be chemically compatible with the drug; - it should not form strongly-bonded complexes with high association constants that will reduce dissolution rates; and - it should be pharmacologically inert. Polyvinylpyrrolidone (PVP) is a water soluble synthetic polymer that fully meets these criteria. Polyvinylpyrrolidone (PVP) is a water soluble synthetic polymer that has been used in the formation of several solid dispersions (3-8). PVP is good matrix material because it undergoes rapid dissolution; it is non toxic; it is compatible with many drugs; and it is pharmacologically inert. PVP appears to aid in bioavailability in three ways: First, the dissolution rates of many poorly soluble drugs are faster from PVP dispersions. Second, PVP appears to form water soluble or water dispersible complexes of indefinite composition with many insoluble or slightly soluble drugs. Third, PVP appears to inhibit or retard the nucleation and crystal growth of drugs once they are dissolved, thus, allowing for the formation of supersaturated solutions. PVP is also notable for the ease with which it forms "complexes" in the solid state with a diversity of drugs. Hydrophobic and hydrogen bonding can play a role in the complexation process because PVP contains hydrophilic (pyrrolidone ring) and hydrophobic (vinyl chain) groups. In most cases, these complexes have a high aqueous solubility depending on copolymer ratio. The objective of this ongoing project is to increase the dissolution rate of griseofulvin (gris), which is an antibiotic, antifungal agent used in the treatment of mycotic diseases of the skin, hair and nails (9). Gris has been shown to be incompletely and irregularly absorbed after oral administration because of its slow dissolution rate in the GI tract (10). In order to improve absorption from the Gl tract, tablets and capsules are formulated to contain microsize crystals of gris. Erratic and incomplete absorption with these formulations can still occur as shown by the sensitivity of gris bioavailability to the dissolution rate of tablets (9). Therefore, a convenient, acceptable and improved dosage form of gris is needed from which the drug is uniformly, rapidly and maximally absorbed in humans. In the present study , the dissolution of gris from PVP dispersions was studied in solutions containing charged and non-charged surfactants. The effect of surfactants was investigated because of their potential to aid in the release of In Tailored Polymeric Materials for Controlled Delivery Systems; McCulloch, I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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drugs. Since the length of carbon chains in a surfactant influences its behavior, all the surfactants used contained a dodecyl chain.


Experimental Materials. Griseofulvin (gris) (Aldrich, USA) with the formula C17H17CIO6 was used as a hydrophobic model drug. Polyvinylpyrrolidone (PVP) (Sigma, USA) with a number-average molecular weight of40,000 was used as the carrier. Both gris and PVP were in powder form when received form the companies and used as received. Methylene chloride (MeCl, Fisher, U.S.A) was used as the solvent in the preparation of the solid dispersions. Sodium dodecyl sulfate (SDS, Aldrich, U.S.A), is an anionic surfactant with the formula of C ^ ^ S C ^ N a , polyoxyethylene dodecylether (Brij-35, Aldrich, U.S.A), is a nonionic surfactant with the formula CH (CH2)ii(OCH CH2)yOH and with y=23, dodecyltrimethylammonium bromide (DTAB, Aldrich, U.S.A), is a cationic surfactant with the formula (CH3)N(CH )iiCH Br, were evaluated in the release studies. 3

2

2

3

Methods. The required amount of polymer and drug were weighed, dissolved in a minimum amount of solvent to obtain a homogeneous solution. Then, the solvent was removed under reduced pressure at 50 ± 2°C on a rotary evaporator. The residue was dried in a vacuum oven at 70 °C overnight. Solid dispersions were prepared from various drug-to-PVP ratios. MeCl had previously been shown to be the best solvent for the preparation of gris-PVP dispersions (H. Akin, J. Heller and F.W.Harris, University of Akron, unpublished data). The each batch of the prepared dispersions was tested for content of the drug. This was done by dissolving a weighed amount of the dispersion in MeCl and the content of the gris was determined spectrophotometrically at 294 nm. Gris was also treated with MeCl to investigate the solvent effect on the drug. Thus, the drug was dissolved in the solvent and then recovered by removing the solvent under reduced pressure. Physical mixtures were also prepared by simply mixing the drug and the PVP in various proportions. Solid Dispersion Characterization Physicochemical Analysis. The physical nature, solid-solid interactions and homogeneity of the solid dispersion systems and physical mixtures were evaluated by differential scanning calorimeter (DSC) and wide angle X-ray diffractometry (WAXD). DSC thermograms were obtained using a DuPont 1090 Differential Scanning Calorimeter equipped with a DuPont 9900 thermal analyzer. Samples contained in DSC aluminum pans (5-10 mg) were heated at a rate of 10 °C/min under a nitrogen atmosphere. WAXD powder patterns were obtained using a Rigaku X-ray generator (40 kV, 150 mA) with a scanning rate of 47min. A rotating anode was the source of the incident X-ray beam. The WAXD pattern was acquired at the diffraction angles, 20, of 10 to 35 . The dried samples were compressed in 4 mm diameter hole of the aluminum sample holder. a

Release Experiments. Release rate experiments were carried out under nonsink conditions. A powdered sample equivalent to 20 mg of gris was dispersed in 400 In Tailored Polymeric Materials for Controlled Delivery Systems; McCulloch, I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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ml of a pH=6.4 phosphate buffer solution. At appropriate intervals, 3 ml samples were withdrawn, filtered through a 0.22 um membrane, and analyzed for gris with UV spectroscopy. All of the release experiments were carried out at 37 °C in a shaker water-bath at 70 strokes/min. For comparison purposes, solvent treated samples of gris were also used in the release experiments. To determine the effect of surfactant on gris dissolution, anionic SDS, cationic DTAB and nonionic Brij-35 surfactants (0.01%) were also added to the release media of the MeCltreated gris sample and solid dispersions Result and Discussion Physicochemical Studies. Pure gris and PVP displayed crystalline and amorphous X-ray patterns, respectively. The sharp diffraction peaks attributed to the gris crystals were maintained in all the physical mixtures. The intensity of the diffraction peaks was dependent on the ratio of gris to PVP. DSC thermograms of gris-PVP physical mixtures exhibits a broad endothermic peak around 70-100 °C, which was attributed to the vaporization of moisture, and an endothermic peak near 220 °C corresponding to the melting point of gris. The intensity of the peak at 220 °C decreased and shifted to lower temperatures with increasing PVP content. Polymorphism was not apparent in the gris samples recovered from MeCl. The X-ray diffraction peaks and the melting points of the gris crystals obtained in this manner were consistent with those of the original crystal powder. The X-ray patterns and DSC thermograms of the solid dispersions are presented in Figures 1 and 2. The sharp diffraction peaks attributed gris crystals disappeared in the X-ray diffraction patterns of the dispersions composed of different gris-to-PVP (w/w) ratios such as 1.3, 1:5, 1:7 and 1:10. The peak at 220 °C which corresponds to the melting point of gris was disappeared in the DSC thermograms of these dispersions. The absence of gris diffraction peaks and the melting peak in X-ray pattern and DSC thermograms, respectively, indicates that was only obtained from the 1:1 ratio of gris-to-PVP. Thus, the ratio of gris-toPVP had to be less than 1:1 in order to obtain amorphous solid dispersions to get better dissolution and water solubility. Release Rate Studies. The release rate of gris from all studied physical mixtures was faster than from those of commercial and MeCl treated gris samples alone. But the initial release of drug from the mixtures was independent of their PVP content. Approximately 26% of the gris in the physical mixtures dissolved in 10 min. However, after this point no additional gris dissolved. The increase in the release rate of grisfromthe physical mixtures may have been due to a surfactant effect of PVP, which increased the wetting of the drug particles. The solvent treated gris samples dissolved slower than commercial gris (received one). Approximately 19.0 % of the commercial gris sample dissolved in 30 min, while only 5.3% of the MeCl-treated samples dissolved during this time. The solid dispersions provided significantly faster drug dissolution than the commercial gris and physical mixtures (Figure 3). In fact, there was rapid saturation of the release medium due to the non-sink conditions. The concentration of the drug exceeded its reported solubility limit (15 mg/L) within a In Tailored Polymeric Materials for Controlled Delivery Systems; McCulloch, I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.


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0) c — Commercial Gris — G r i s / P V P : 1/5 Gris/PVP: 1/1 Gris/PVP: 1/7 * - Gris/PVP: 1/3 - • - Gris/PVP: 1/10 Figure 3. Gris dissolution from solid dispersions



0

100

200 300 TIME (min)

400

—®— Commercial Gris Gris/PVP" 1/5 Gris/PVP: 1/1 - a - Gris/PVP: 1/7 —^— Gris/PVP: 1/3 Gris/PVP: 1/10 Figure 4. Effect of an anionic surfactant on the release of gris



220

0

V 0

1 100

1 200

1 300

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TIME (min)

—•— Commercial Gris —*— Gris/PVP: 1/7 —•— Gris/PVP: 1/3 —* ~ Gris/PVP: 1/5 -®— Gris/PVP: 1/1 —©- Gris/PVP: 1/10 r

Figure 5. Effect of a cationic surfactant on the release of gris



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100

0

100

200

300

400

TIME (min) —®— Commercial Gris —e— Gris/PVP: 1/5 —a— Gris/PVP: 1/1 Gris/PVP: 1/7 - a - Gris/PVP: 1/3 - @ - Gris/PVP :1/10 Figure 6. Effect of a non-charged surfactant on the release of gris


222 the anionic surfactant, the rates were still significantly increased. The effect was noticeable for the 1/5, 1/7, and 1/10 gris-to-PVP solid dispersions where the amount of gris released was twice that of the gris released in the absence of the surfactants.


Conclusion Amorphous dispersions of gris in PVP can be prepared from MeCl solutions. However, the ratio of gris-to-PVP has to be less than 1:1 (w/w) in order to prevent the gris from undergoing crystallization. The T of the PVP is significantly decreased in the dispersions suggesting that there are strong interactions between the drug and PVP. The amount of gris released from the dispersions in a phosphate buffer solution increases as the ratio of gris-to-PVP decreases from 1:1 to 1:5. The amount of gris released is not increased by further increases in the amount of PVP. The maximum amount of gris released in % 40 in 400 minutes is 2 times greater than the amount of gris released from pure gris powder in the same time period. Anionic, cationic and non-charged surfactants in the buffer enhance the dissolution rate and increase the amount of gris released. g

Acknowledgement The support of this research by Advanced Polymer Systems is gratefully acknowledged. References 1. 2. 3. 4. 5. 6. 7. 8. 9.

W.L.Chiou and S.Riegelman, J.Pharm.Sci., 1971, 60, 1281. K. Sekiguchi and N. Obi, Chem. Pharm. Bull., 9, 866-872, 1961. B.J.Hargreaves, J.E.Pearson, P.Connor, J.Pharm.Pharmacol., 1979, 31, 47P. A.P.Simonelli, S.C.Mehta, W.I.Higuchi, J.Pharm. Sci., 1969, 58, 538. B.A.Bolton, P.N.Prasad, J.Pharm.Sci., 1984, 73(12), 1849. R.Jachowicz, Int.J.Pharm., 1987, 35, 1. A.Hoelgaard, N.Moeller, Arch.Pharm.Chemi., Sci.Ed., 1975, 3(3), 67. A.P.Simonelli, S.C.Mehta, W.I.Higuchi, J.Pharm.Sci., 1976, 65(3), 355. N. Aoyagi, H. Ogata, N. Kaniwa, M. Koibuchi, T. Shibazaki, A. Ejima, J.Pharm.Sci, 1982, 71(10), 1165. 10. H. Blank, Am. J. Medicine, 39, 831, 1965.


Effect of Surfactants on the Release of Griseofulvin from

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