OR WAIT null SECS
The main techniques employed in the pharmaceutical field for the manufacturing of coated solid dosage forms are based on the deposition of different materials onto substrate cores from solutions or suspensions. Therefore, the evaporation of large amounts of liquids (no less than 70% w/w with respect to coating material) is required. Aqueous coating systems were first proposed to replace organic solvents, which involve toxicological, environmental and safety-related drawbacks, that are likely to impact on manufacturing costs.1–3 For the same reasons, methods for the production of loaded pellets by the layering of drug-containing aqueous formulations were also developed. However, the need for water removal also necessitates time- and energy-consuming drying phases and could cause drug instability issues.
To overcome the problems associated with the use of water, a number of new coating procedures — or the innovative applications of well established ones — have been proposed during the last two decades, and are generally referred to as dry coating techniques.4,5 The dusting method for the application of sugar coatings or the powder layering technique for the manufacturing of drug-loaded pellets represents early attempts to lessen the amount of water employed in coating or coating-like processes.6–11 In the case of powder layering, the amount of solvent to be removed is reduced to less than 50% w/w with respect to coating material. The role of water is, in fact, limited to that of a solvent for wetting/binding formulations that are sprayed onto inert seeds only to promote the adhesion of a drug powder blend. An analogous coating is used for the manufacturing of a time- and site-controlled drug delivery system (chronotopic), provided with a swellable hydrophilic polymeric layer (hydroxypropyl methylcellulose) that is able to delay the onset of release.12
In this article, an attempt is made to review and classify the variety of dry coating approaches. Dry coating only refers to coating techniques that avoid the use of water or, at least, allow it to be reduced to very small amounts with respect to the coating material, thus limiting the expected impact of an incidental solvent evaporation step. According to such a classification, techniques are divided into liquid-based and powder-based techniques, depending on the physical status of coat forming agents when layered onto the substrate (Figure 1). A second classification tier is based on how coat formation/consolidation is achieved. As far as powder-based techniques are concerned, a further subdivision is made that takes into account whether or not liquid adjuvants are used, which generally consist of plasticizers or binding solutions intended to promote the adhesion of powder particles onto the core surface and/or the formation/consolidation of the coating.
Liquid-based dry coating processes involve the deposition of nonaqueous liquid materials and their subsequent consolidation in a continuous layer.8,13–16 Such liquids may be molten formulations that are expected to solidify by cooling (hot melt coating technique), or liquid precursors that undergo polymerization directly on the core surface (polymerization coating technique).
Hot melt coating processes are generally carried out in fluid bed equipment and require the liquid coating agent to be maintained at a temperature of 40–60°C above its melting point.8,13 Only thermally stable materials with a relatively low melting point (<80°C) can be used, such as fats, waxes or high molecular-weight polyethylene glycols. The most common applications of this technique include the coating of pellets, granules and powder particles, particularly to obtain moisture-protected or modified-release dosage forms.
The polymerization coating technique appears to have very limited potential for use in the pharmaceutical field because of technical and toxicological reasons. However, it has been employed to apply functional coatings onto drug particles and pellets. The polymerization process is caused by a UV-activated chemical reaction of functionalized liquid precursors (prepolymers or monomers) in the presence of an initiator.14 An extremely rapid transition of the system from liquid to solid, which occurs at or below room temperature, leads to the formation of the coating (photo curing phase). An analogous coating technique based on the use of gaseous formulations (vapours of monomers and primary radicals of initiators) has recently been described for the encapsulation of fine particles (initiated chemical vapour deposition, iCVD).15,16 According to the monomer selected, coatings with differing characteristics can be obtained, such as enteric films composed of acrylic resins.
The formation of a layer around a core, starting from solid particulate materials, can be performed by means of compaction, exploiting well known tableting methods, or by heat curing following powder layering.
Press coating, also referred to as double compression coating, compression coating or dry coating, is a rather dated technique that was first proposed by Noyes in an 1896 patent. The industrial application of this technique began in the late 1950s following the development of purposely designed tableting machines.17–19 Press coating involves the compaction of a defined amount of a powder formulation applied around a tablet core that is usually prepared using the same equipment. Any type of material with adequate compaction properties can be used for the coating. More recently, drug delivery systems based on compression-coated functional layers have been proposed for pulsatile or prolonged release of active ingredients.20–23 However, many difficulties are encountered in the manufacturing of press-coated systems, in particular the centring of the core in the die to ensure uniform coating thickness. Further constraints include the requirement for complex equipment, the formation of relatively thick layers and the limited range of viable core dimensions.
More recently proposed powder-based dry coating techniques exploit heating treatments that induce particle modifications (i.e., melting and glassy-rubbery transition) and promote the formation of the final coating layer. These kinds of techniques can be further classified — based on whether liquid systems are added to help particle deposition during the layering phase and/or achieve the final coating formation/consolidation during the curing step.
When powder formulations are involved in a dry coating process, two common steps need to be faced — the distribution of a powder blend onto the substrate and its turning into a continuous coating. With regard to the first step, procedures developed in conventional coating equipment (i.e., fluid bed and coating pan) often make use of adapted powder-feeding devices (Figure 2). In these cases, the flow properties of the powder formulation should be regarded as critical. Some authors suggest alternative approaches based on the simultaneous fluidization of core particles and low melting coating powders (fluid bed apparatus or hot air operated venturimeter).24,25 By increasing the inlet air temperature to above the melting point of the coating material, a liquid is obtained that can be spread onto the surface of the cores. Solidification of the coat is then achieved by cooling.
Various means of improving the distribution of powder particles onto the substrates are described in the literature. In this respect, the electrostatic attraction between oppositely charged coating particles and substrate surfaces is exploited.26–30 LeQtracoat technology, for example, was developed for tablet coating based on the same principles that are used for the deposition of ink toner in electrophotography (photocopying).28 Tablets are coated individually one side at a time in special manufacturing plants with a capacity of up to 250000 units/h. With this technique, the coat-forming agent may be directed with such precision that images can be created on the tablet surface.
In another coating technique, the use of a preheating phase (IR source) is proposed to improve particle adhesion onto tablet cores through the partial softening/melting of acrylic polymeric particles (Eudragit EPO).31 A similar approach involves the preliminary deposition of a low melting material, the solid–liquid transition of which (the preheating step) can prime adhesion of the subsequently added coat forming agent.32,33 Furthermore, the adhesion of particles onto the core surface can be ensured by spraying small amounts of aqueous binding solutions alternately or concurrently with the powder distribution.34–36 With the aim of completely avoiding the use of water in the coating process, some authors demonstrated the effectiveness of liquid plasticizers or mixtures of plasticizers compared to aqueous binding solutions.37–40 In these cases, adjuvants have a twofold advantage as they are also involved in the formation/consolidation of the coat.
When powders alone are employed, the coating formation step starts with particle sintering and coalescence triggered by raising the temperature above the glassy-rubbery transition temperature of the coat-former.41 As a result, the surface tension and capillary pressure difference of the molten material tend to round any liquefying particles and drive the flow from smaller to larger ones. By rearrangement of the particles, trapped air is likely to be removed, which leads to the formation of a uniform and continuous coat. The initial presence of liquid adjuvants in the coating formula or, in some cases, their introduction in small amounts during the heat-treatment, may lead to a change in the coat-forming mechanism.
Tables 1 and 2 give an overview of the most representative powder-based dry coating applications. Following the classification set out in this review, techniques are arranged according to the composition of the coating formulation, that is, powder alone (Table 1) and powder and liquid adjuvants (Table 2).
The large number and diversity of dry coating approaches reviewed confirm the increasing interest towards avoiding the use of water within the coating of solid cores. Advantageous applications have been described with respect to process time, overall manufacturing costs and ability to overcome water-induced degradation of active ingredients. Indepth knowledge of the mechanisms of coating formation and, in some cases, availability of suitable coat-forming agents and industrial-scale equipment should be regarded as the main issues for the consolidation of dry coating technology in the pharmaceutical field.
1. T. Nagai et al., "Application of HPMC and HPMCAS to aqueous film coatings of pharmaceutical dosage forms," in J.W. McGinity, Ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Volume 7 (Marcel Dekker, New York, NY, USA, 1997), 177–225.
2. C. R. Cunningham and K. A. Fegely, Pharm. Technol. Eur.13(10), 48–54 (2001).
3. S. C. Porter, "Coating of pharmaceutical dosage forms," in P. Beringer et al., Eds, Remington: the Science and Practice of Pharmacy (Lippincot Williams & Wilkins, Philadelphia, PA, USA, 2006), 924–938.
4. R. Bodmeier and J. W. McGinity, Drug Deliv. Tech., 5(9), 70–73 (2005).
5. E. Teunou and D. Poncelet, "Dry coating," in C. Onwulata, Ed. Encapsulated and Powdered Foods, Volume 146 (CRS Press, Boca Raton, FL, USA, 2005), 179–195.
6. Y. Tomida and M. Saeki, Drug Dev. Ind. Pharm., 25(1), 21–27 (1999).
7. S. Ohmori et al., Chem. Pharm. Bull, 52(3), 322–328 (2004).
8. J. Swabrick and J. C. Boylan, Eds, Encyclopedia of Pharmaceutical Technology, Volume 3 (Marcel Dekker, New York, NY USA, 2002), 2068–2071.
9. C. Nastruzzi et al., AAPS PharmSciTech, 1(2), E9 (2000).
10. V.K. Gupta et al., Int. J. Pharm., 213(1–2), 83–91 (2001).
11. N. Sinchaipanid et al., Pharm. Dev. Technol., 9(2), 163–170 (2004).
12. M. Cerea et al., "Powder-layering technique for the preparation of the HPMC-based retarding coating of an oral system for pulsatile and/or colon-specific release", AAPS Annual Meeting and Exposition (Salt Lake City, UT, USA, 2003), W5135.
13. N. Sinchaipanid et al., Powder Tech., 141, 203–209 (2004).
14. S. Bose et al., J. Pharmaceutical Innovation, 1(1), 44–53 (2006).
15. K. K. Lau and K. K. Gleason, Macromol. Biosci., 7(4), 429–434 (2007).
16. T. P. Martin et al., Biomaterials, 28(6), 909–915 (2007).
17. P. J. Noyes, "An improved pill or tablet machine", Patent GB8599.
18. F. C. Blubaugh et al., J. Am. Pharm. Assoc., 47(12), 857–862 (1958).
19. B. Korsatko-Wabnegg, Pharmazie, 45(11), 842–844 (1990).
20. A. Gazzaniga et al., Eur. J. Pharm. Biopharm., 40(4), 246–250 (1994).
21. E. Fukui et al., Int. J. Pharm., 204(1–2), 7–15 (2000).
22. M. Qi et al., Drug Dev. Ind. Pharm., 29(6), 661–667 (2003).
23. S. Y. Lin et al., AAPS J., 6(3), 1–6 (2004).
24. J. P. Kennedy and P. J. Niebergall, Pharm. Dev. Technol., 3(1), 95–101 (1998).
25. L. Rodriguez et al., Drug Dev. Ind. Pharm., 30(9), 913–923 (2004).
26. J. E. Hogan et al., "Powder coating composition for electrostatic coating of pharmaceutical substrates," Patent EP 1075838 (1996).
27. M. Walton et al., "Effects of charging times on charge distributions powders for electrostatic deposition onto oral drug delivery systems," AAPS Annual Meeting and Exposition (Toronto, ON, Canada, 2002), T3211.
28. Phoqus Pharmaceuticals Limited, Press release (2005) www.phoqus.com
29. A. Jarvis et al., "Method and apparatus for the application of powder material to substrates," Patent GB 2425977 (2006).
30. J. Zhu et al., "Direct coating solid dosage forms using powdered materials," Patent WO 014468 (2007).
31. M. Cerea et al., Int. J. Pharm., 279(1–2), 127–139 (2004).
32. W. Zheng et al., J. Drug Deliv. Sci.Tech., 14(4), 319–325 (2004).
33. D. Sauer et al., Eur. J. Pharm. Biopharm., 67, 464–475 (2007).
34. N. Pearnchob and R. Bodmeier, Pharm. Res., 20(12), 1970–1976 (2003).
35. N. Pearnchob and R. Bodmeier, Int. J. Pharm., 268(1–2), 1–11 (2003).
36. N. Pearnchob and R. Bodmeier, Eur. J. Pharm. Biopharm., 56(3), 363–369 (2003).
37. S. Obara et al., Eur. J. Pharm. Biopharm., 47(1), 51–59 (1999).
38. M. Cerea et al., "Feasibility study on enteric coating of solid dosage forms by powder layering with HPMCAS," World Meeting ADRITELF/APGI/APV (Florence, Italy, 2002), 171.
39. E. Ivanova et al., J. Food Eng., 71, 223–230 (2005).
40. C. D. Kablitz et al., Eur. J. Pharm. Sci., 27(2–3), 212–219 (2006).
41. Z. Huang and W. Eklund, "Film formation in powder coatings," Waterborne, Higher-Solids and Powder Coatings Symposium (New Orleans, LA, USA, 1997), 328–341.
Matteo Cerea is assistant professor.
Lucia Zema is assistant professor.
Luca Palugan is assistant professor at the University of Milan, School of Pharmacy (Italy).All are part of a pharmaceutical technology research team whose main interests are related to the design, manufacturing and evaluation of oral drug delivery systems.
Andrea Gazzaniga is full professor at the University of Milan, School of Pharmacy, where he supervises the activities of a pharmaceutical technology research team. He is part of a group of experts of the European Pharmacopeia and an official consultant to the Italian agency for medicinal products (AIFA). He serves on the editorial board of various international journalists. In 2004 he as elected to Fellow of American Association of Pharmaceutical Scientists (AAPS).