Dropping Method Solution for Formulating Solid Dispersions

Since the early 1960s, solid dispersion systems have been used to increase the rate of dissolution and bioavailability of poorly water-soluble drugs.1 Solid dispersions of drugs are generally produced by either solvent evaporation or melt methods.2

Both procedures require further processing. After production by solvent evaporation, the solvent is removed and the dispersions are hardened then usually pulverized, sieved and mixed. Solid dispersions produced by the melt method are hardened at low temperatures before the pulverizing, sieving and mixing stages.

Solvent evaporation

This method involves dissolving the drug and carrier in a common organic solvent, and then removing the solvent by evaporation. Chiou and Riegelman3 used 500 mL of ethanol to dissolve 0.5 g of griseofulvin and 4.5 g of polyethyleneglycol (PEG) 6000. To prepare a piroxicam-PEG 4000 solid dispersion, Fernandez et al.4 dissolved the drug in chloroform and then mixed the solution with a melt of PEG 4000 at 70 °C.

Figure 1-4.

Many different methods (including spray- and freeze-drying) have been used to remove organic solvents from solid dispersions. Simonelli et al.5 evaporated the ethanolic solvent with a steam bath and removed the residual solvent by applying reduced pressure. Chiou and Riegelman dried an ethanolic solution of griseofulvin and PEG 6000 in an oil bath at 115 °C until ethanol bubbles were no longer formed. The viscous mass was then solidified by cooling it in a stream of cold air.

Removal of organic solvents such as chloroform from large masses of material may be difficult because the solid dispersions are usually amorphous and may be viscous and waxy. Additional problems may be residual solvent, the cost of recovering the solvents and the further processing (such as pulverization and sifting) of the solidified product.

The melting method

In 1961, Sekiguchi and Obi6 formed eutectic mixtures of drugs with water-soluble carriers by melting their physical mixtures. This was a significant advance in the development of solid dispersion systems. They prepared solid dispersions of sulfathiazole in carriers such as ascorbic acid, acetamide, nicotinamide, nicotinic acid, succinimide and urea by melting various drug -- carrier mixtures. Eutectic mixtures of the drug with carriers were used to minimize melting temperatures. Various methods were used to harden the melts. Sekiguchi and Obi used an ice bath with vigorous stirring until the melt solidified. Chiou and Riegelman spread a griseofulvin -- PEG 6000 solid dispersion on a stainless steel plate and blew cold air over it, then stored the material in a desiccator for several days. Timko and Lordi7 applied blocks of dry ice to cool and solidify phenobarbital -- citric acid melt mixtures.

Figure 5.

Semisolids and waxes are usually used as carriers in the melt method. Developing the dosage form of such materials can be difficult because it is hard to pulverize and sift the dispersions. They are usually soft and tacky, with poor flow and mixing properties as well as poor compressibility, and may not be amenable to processing by tablet machines.

Currently, the melting method is known as 'hot melt technology,' and provides pharmaceutical technologists with new possibilities. This article discusses current melting methods and describes the dropping method, a promising new hot melt technology.

Direct melt filling

In 1978, Francois and Jones8 further developed the solid dispersion method by directly filling hard gelatin capsules with semisolid materials as a melt, which solidified at room temperature. Chatham9 reported the possibility of preparing PEG-based solid dispersions by filling drug–PEG melts into hard gelatin capsules.

Serajuddin et al.10 demonstrated that PEG itself might not be a suitable carrier for the solid dispersion of poorly water-soluble drugs intended for direct filling into hard gelatin capsules. At room temperature, solid plugs were formed inside the capsules where the dissolution of the drug from PEG-based solid dispersions was incomplete. The water-soluble carrier dissolved more rapidly than the drug, and drug-rich layers were formed over the surfaces of the dissolving plugs, preventing further dissolution of the drug from solid dispersions.

Figure 6.

Studies report that complete dissolution of the drug from solid dispersions can be achieved using surface- active or self-emulsifying carriers, but only a small number of such carriers are currently available for oral use. The temperature of the melt should not exceed 70 °C during filling, which is the maximum acceptable temperature for most hard gelatin capsules. Some of the manufacturing problems mentioned earlier may be encountered in the direct capsule filling method. Despite the difficulties, however, the method is used to produce animal preparations.

Melt extrusion

Melt extrusion is a new method for producing solid dispersions. Special equipment is needed to develop the dosage form from solid dispersions, which limits the use of the extrusion method. Forster et al.11 report the use of melt extrusion to prepare glass solutions of poorly water-soluble drugs with hydrophilic excipients. It is claimed that the method is an improvement to existing formulation methods such as spray-drying and co-melting because it uses smaller quantities of drug, reduces particle size and speeds up the formulation process.

Dropping method

The dropping method, developed by Ulrich et al.12 to facilitate the crystallization of different chemicals, is a new procedure for producing round particles from melted solid dispersions. This technique may overcome some of the difficulties inherent in the other methods.

Laboratory-scale preparation. A solid dispersion of a melted drug– carrier mixture is pipetted and then dropped onto a plate, where it solidifies into round particles (Figure 1). The size and shape of the particles can be influenced by factors such as the viscosity of the melt and the size of the pipette. Because viscosity is highly temperature-dependent, it is very important to adjust the temperature so that when the melt is dropped onto the plate it solidifies to a spherical shape.

Figures 2 and 3 show samples of round particles made by the dropping method. The round particle in Figure 2 is made from melted PEG 4000 alone (Fluka AG, Buchs, Switzerland), which solidifies at room temperature. The use of carriers that solidify at room temperature may aid the dropping process. Figure 3 shows a round particle dropped from a solid dispersion of a melted drug–carrier mixture, and Figure 4 shows a batch of round particles prepared at laboratory scale by the equipment illustrated in Figure 1. The particles, dropped at 58 °C onto a stainless steel plate, have a diameter of 2.5 mm (60.13 mm). The temperature of the plate was adjusted to room temperature (20 °C 61 °C). Stainless steel was chosen because of its optimal surface energy (30.17 mN/m), which results in the formation of round particles.

Figure 7.

In vitro dissolution studies. Solid dispersions of a poorly water-soluble drug were prepared by three different methods to compare their dissolution rates. Dissolution tests were performed using a Pharmatest (Hainburg, Germany) dissolution tester,13 set with a paddle speed of 100 rpm. Artificial enteric juice (900 mL) with a pH of 7.5 (60.1) at 37 °C (60.5 °C) was used. Samples were withdrawn at 5, 10, 15, 20, 30 and 60 minutes, and were assayed spectrophotometrically at 280 nm (Helios a; Spectronic Unicam, Cambridge, UK) after filtering.

The results are shown in Figure 5. Samples in Series 1 are solid dispersions made by the dropping method, Series 2 shows those made by direct capsule filling and Series 3 those made by a conventional (pestle and mortar) melting method. The results of the dissolution tests show that the solid dispersions made by the dropping method have better drug-release properties than those produced by the other two methods, particularly during the first 20 min. This shows that using the dropping method not only simplifies the manufacturing process, but also gives a higher dissolution rate.

Advantages of the dropping method. The dropping method does not use organic solvents and, therefore, has none of the problems associated with solvent evaporation. The method also avoids the pulverization, sifting and compressibility difficulties encountered with the other melt methods. Figure 6 compares the different melting methods for producing solid dispersions.

Disadvantages of the dropping method. Only thermostable drugs can be used and the physical instability of solid dispersions is a further challenge.

Future and industrial scale. Despite many results demonstrating improved bioavailability of poorly water-soluble drugs using solid dispersion systems, manufacturing and scale up has always been difficult. Figure 7 illustrates equipment (Rotoform; Sandvik Process Systems Co, Sandviken, Sweden) that can be used to produce solid dispersions by the dropping method at an industrial level.14

Conclusion

Although there is still much work to do in this field (better size distribution, uniformity and stability), the dropping method is a promising approach in the formulation of solid dispersions. Simplifying the formulation process for the dropping method may overcome manufacturing difficulties.

Acknowledgments

The authors are grateful to Professor Joachim Ulrich (Martin-Luther-University, Halle-Wittenberg, Germany) for providing facilities.

References

1. A.T.M. Serajuddin, "Solid Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs," J. Pharm. Sci. 88, 1058-1066 (1999).

2. F. Damian et al., "Physical Stability of Solid Dispersions of the Antiviral Agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30," Int. J. Pharm. 244, 87-98 (2002).

3. W.L. Chiou and S. Riegelman, "Preparation and Dissolution Characteristics of Several Fast-Release Solid Dispersions of Griseofulvin," J. Pharm. Sci. 58, 1505-1509 (1969).

4. M. Fernandez et al., "Characterization of Solid Dispersions of Piroxicam/poly-(ethylene glycol) 4000," Int. J. Pharm. 84, 197-202 (1992).

5. A.P. Simonelli, S.C. Mehta and W.I. Higuchi, "Dissolution Rates of High Energy Poly(vinylpyrrolidone) (PVP)-Sulfathiazole Co-precipitates," J. Pharm. Sci. 58, 538-549 (1969).

6. K. Sekiguchi and N. Obi, "Studies on Absorption of Eutectic Mixture. A Comparison of the Behavior of Eutectic Mixture of Sulfathiazole and that of Ordinary Sulfathiazole in Man," Chem. Pharm. Bull. 9, 866-872 (1961).

7. R.J. Timko and N.G. Lordi, "Thermal Characterization of Citric Acid Solid Dispersions with Benzoic Acid and Phenobarbital," J. Pharm. Sci. 68, 601-605 (1979).

8. D. Francois and B.E. Jones, "The Hard Capsule with the Soft Center," European Capsule Technology Symposium, Constance (11-13 October 1978) pp 55-61.

9. S. M. Chatham, "The Use of Bases in SSM Formulations," S.T.P. Pharm. 3, 575-582 (1987).

10. A.T.M. Serajuddin et al., "Effect of Vehicle Amphiphilicity on the Dissolution and Bioavailability of a Poorly Water-Soluble Drug from Solid Dispersions," J. Pharm. Sci. 77, 414-417 (1988).

11. A. Foster, T. Rades and J. Hempenstall, "Selection of Suitable Drug and Excipient Candidates to Prepare Glass Solutions by Melt Extrusion for Immediate Release Oral Formulations," Pharm. Technol. Eur. 14(10), 27-37 (2002).

12. H.C. Býnd J. Ulrich, "Parameters Influencing the Properties of Drop-Formed Pastilles," in J. Ulrich, Ed., CGOM4 (Shaker Verlag, Aachen, Germany, 1997) pp 123-130.

13. European Pharmacopoeia, 4th Edition, EDQM, Council of Europe, Strasbourg, France (2002).

14. Sandvik Process Systems, "Rotoform-Verfahren zur Herstellung von Pastillen," Die chemische Produktion 3, 50-52 (1988).