Dry powder coating of pharmaceuticals: A review

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS International Journal of Pharmaceutics xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Review

Dry powder coating of pharmaceuticals: A review Dorothea Sauer a , Matteo Cerea b , James DiNunzio c , James McGinity d,∗ a

Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche “M.E. Sangalli”, via G. Colombo 71, 20133 Milano, Italy c Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110-1199, United States d College of Pharmacy, The University of Texas at Austin, 1 University Station A1900, Austin, TX 78712, United States b

a r t i c l e Article history: Available online xxx Keywords: Dry powder coating Film coating Curing Rotor granulation Fluid bed Melt extrusion Polymer Plasticizer Adhesion

i n f o

a b s t r a c t Over the last half century, film coating technology has evolved significantly in terms of compositions and manufacturing processes, allowing for greater functionality, flexibility and efficiency. Driven by a combination of cost considerations and functionality, a range of dry powder coating technologies have been developed in both academic and industrial settings. These technologies can be generally classified into three major types based on the layer formation process: liquid assisted, thermal adhesion and electrostatic. In addition to specific manufacturing processes that must be implemented to achieve the desired product attributes, many of these techniques also require the use of novel excipients and specific formulations to provide acceptable manufacturability. This review summarizes the current dry powder coating technologies and highlights their industrial applicability with publicly disclosed case studies. Commentary on the future directions of dry powder coating is also provided. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

4.

5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Film formation mechanisms in dry powder coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid assisted coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Processing equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Formulation case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thermal adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Processing equipment considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Formulation case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrostatic coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Process equipment considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Formulation considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current trends and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Conventional technologies for the application of film coatings onto pharmaceutical dosage forms involve the atomization of polymeric systems dispersed as solution or suspension in volatile organic solvent(s) and/or aqueous vehicles. While the use of organic solvents is generally faster with simplified film formation processes

∗ Corresponding author. Tel.: +1 512 471 4843; fax: +1 512 471 2746. E-mail address: [email protected] (J. McGinity).

00 00 00 00 00 00 00 00 00 00 00 00 00

because of the dissolved nature of the polymer, the use of aqueous systems remains the preferred manufacturing approach due to the absence of solvent toxicity, increased process safety and lower manufacturing costs. Even in light of the benefits of aqueous systems, there are several cases where aqueous systems are inappropriate and organic solvent coatings may be necessary. This is particularly true when the pharmaceutical ingredient is sensitive to water, and organic solvents are used to prevent this issue. In addition to degradation of the active ingredient, migration of water with aqueous systems may occur during the coating process or during storage thus compromising the quality of the finished

0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15 2

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

product. The need to avoid aqueous and organic solvents may be particularly critical if the drug product is formulated as an amorphous solid dispersion. From a process standpoint aqueous coatings require both a substantial amount of water, as well as energy to evaporate the water during manufacturing. While thermal energies to drive evaporation of solvents may be lower, the need for environmentally friendly and safe solvent recovery significantly increases costs around solvent operations (Bose and Bogner, 2007). Overall, this leads to longer processing times and greater overhead costs for conventional film coating operations. These issues, associated with both aqueous and organic coatings, have led to the adoption of dry powder coating techniques in a number of other industries. Within the pharmaceutical industry, several alternative technologies have been recently proposed in order to reduce the use of water or organic solvents during the coating process. Among these are technologies which range from the atomization of molten materials, commonly known as melt coating, to softened powder layering and electrostatic adhesion (Cerea et al., 2008a). The melt coating process requires the application of low melting point materials maintained at temperatures of about 40–60 ◦ C above the melting point of the wax or polymeric component. When fatty-acids of glycerol esters or low melting polymers such as polyethylene glycols are applied, the melt coating is performed in a fluid bed coater with the aid of heating systems for atomized air to provide a molten spray plume. Unlike conventional fluid bed coating which uses heated gas to remove solvent, inlet air will enter the system for melt coating at a reduced temperature to solidify the molten coating on the substrate. During manufacture, engineering controls including pipeline insulation are utilized to prevent the solidification of the molten material before the final cooling takes place on the surface of the coating cores. Recently, this technology has also been used for particle engineering through the application of spray drying and melt spray congealing processes (Ilic´ et al., 2009; Lo et al., 2009). While melt coating is considered a solvent free process and used in the manufacture of at least one commercial product, it falls outside of the scope of this review which deals with dry powder methodologies. Implementing a similar strategy, liquid assisted layering strategies rely on interfacial capillary action of liquid formulation components to aid in the adhesion of the coating layer onto the substrate. In these technologies, the liquid additive can be partially mixed into the feedstock or added as a separate feed stream into the processing zone. Based on the process similarity with conventional strategies, existing equipment, specifically fluid beds, can easily be modified to support production, although formulations of this type will typically require higher levels of plasticizer or tackifying agent. Longer processing times and additional post processing curing steps may also be required. Process and manufacturing equipment designs will also be similar, although the choice of excipients will be governed by thermal properties of the coating materials to provide sufficient softening at moderate temperatures while still providing suitable mechanical properties at room temperature. Adhesion, plastic deformation and consolidation will all be critical points to consider during formulation design. Electrostatic modalities differ from the other forms of dry powder coating both in terms of excipients as well as manufacturing equipment. For successful coating, the material must be conductive to allow for charge differential formation while exhibiting desired film forming characteristics. Electrostatic coating equipment creates specific charge fields allowing for the coating of complex designs that cannot be achieved with traditional systems. Using commercial scale electrostatic coaters production outputs comparable to conventional systems can be achieved. Overall, success with many of these alternate solvent free techniques has been demonstrated for a number of applications. While many of these technologies have reached industrial manufacturing

scales, the adoption into commercial production of drug products has been slow. This review highlights the principles of dry powder coating and presents recent examples where the technology has been applied. 2. Film formation mechanisms in dry powder coating From a mechanistic perspective, dry powder coating processes consist of the same sequence of steps that are employed with conventional solvent based coatings. In all cases the process begins with the pretreatment of coating material. This is followed by the application of coating material to the substrate, relying on the adhesive nature of the formulation to maintain uniformity of coating during the film formation process. Film formation occurs by a process of evaporation, coalescence and sintering which are influenced by process and formulation considerations. As the amount of volatile solvent used approaches zero the evaporation process may be neglected, as is the case for many dry powder applications. Pre-treatment of the coating material varies greatly based on the type of coating process utilized. For dry powder coating applications, careful consideration of material particle size will be essential to ensure appropriate uniformity for the coating. It is generally recommended that coating material diameter be less than 1% the size of the coating substrate. This allows for acceptable uniformity of the material on the substrate surface, improving adhesion, appearance and processing times. During the dry powder coating process, the substrates are often heated above the glass transition temperature of the layering materials so that the coating materials soften and adhere to the substrate. For conventional film coating, spreading and adherence is well defined based on surface free energies and capillary forces where mobility is not a limiting interaction. However, powder systems may become limited by mobility, particularly when liquid levels are reduced to the point where solid particle deformation becomes rate limiting. This introduces a series of constraints related to mechanical and thermal properties of the coating formulation. Coalescence and film formation, which are highly dependent on capillary forces in conventional coating systems, will also be dependent on these properties. As such, glass transition temperature and plastic deformation characteristics of the coating materials are paramount to the success of the process and if materials are deficient in these properties then it may be necessary to engineer the formulations with the desired characteristics. Many pharmaceutical coating materials are amorphous polymers, exhibiting a glass transition temperature related to the change from a glass to a supercooled liquid. On transition, which occurs at a specific temperature, mobility of the system increases significantly. The greater mobility allows for molecular rearrangement and alters the plastic deformation characteristics of the materials. A generalized equation for prediction of the glass transition temperature of a mixture of materials is the Fox equation, shown in Eq. (1):

w 1 i = Tg Tg,i n

Fox equation for approximation of

i=1

glass transition temperature

(1)

where wi is the weight fraction of individual components and Tg,I is the glass transition temperature of the individual components. Based on the weight fraction of the components (wi ) and respective glass transition temperatures (Tg,i ) it is possible to estimate the resulting glass transition temperature. Through the addition of low glass transition materials one can reduce the glass transition of the overall composition, a common approach in many dry powder coating formulations to improve coalescence and adhesive properties.

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

Other more detailed approaches, such as the Gordon–Taylor equation, can also be used for estimation of the resulting glass transition temperature (Gordon and Taylor, 1952). When processing above the glass transition temperature of a coating material, the surface is more “liquid-like” and more susceptible to plastic deformation. Depending on the difference between glass transition temperature and processing temperature, the viscosity of the coating material can be reduced sufficiently to result in the formation of capillary forces which aid in the adherence of the powder to the surface. Under such conditions, surface energy differentials can aid in the spreading of the semi-molten polymer to enhance coating efficiency. Dry powder coating applications also rely on mechanical compaction that occurs naturally during the process to facilitate adhesion and coalescence. During this process stresses on the coating layer result in consolidation of the bed and deformation driven spreading across the interface. For elastic materials, the deformation of the material is reversible, leading to poor contact across the surface. When coatings exhibit plastic behavior, the deformation is irreversible and the mechanical compaction leads to greater adhesion of the surface layer due to a larger surface area for contact between substrate and coating, as well as possible mechanical interlocking of the materials. Adhesion and spreading behavior can also be modified through the application of a sub-coat to the substrate. This allows for a change of interfacial energy by the application of a new material that can facilitate adhesion of powder coat. The subcoating layer corresponding to 2–3% weight gain of the uncoated core has been reported (Cerea et al., 2004). Low melting point, hydrophilic polymers (polyethylene glycol 3350) have been extensively used in the literature, however, other materials, with amphiphilic and hydrophobic properties (Pluronic 127, Cetylstearyl Alcohol) have also been reported (Zheng et al., 2004). To further promote adhesion with the coating layer, the subcoat can actually be intentionally selected to be partially molten at the processing temperatures. The molten priming layer promotes the adhesion of the powder coating particles by forming liquid bridges with the tablet surface. The interfacial interactions between the tablet surface and the polymer particle are rather complex and depend on interfacial tension, wetting and adhesion (Grundke et al., 1996). Since the spreading of the priming layer on the surface of the coating cores is crucial, the best subcoating material is selected by measuring the contact angle with water of the tablet surface and those of the primer and of the polymeric material to be layered (Sauer et al., 2007; Sauer and McGinity, 2009a). The closer the contact angle values, the more efficient will be the adhesion of the powder to the surface. The mechanism of film formation of the powders layered onto the solid cores can be summarized by (i) coalescence and sintering of the particles of the polymeric materials in a process that involves the partial fusion of the polymer; (ii) leveling of the coating material includes densification of the layer with reduction of the empty spaces and smoothing of the surface; (iii) cooling of the layer and hardening of the coating. A schematic of this process is shown in Fig. 1. In conventional coating applications, coalescence is driven by the presence and subsequent removal of solvent which creates capillary forces inside the film and lowers the glass transition temperature of the polymer. The mechanism for coalescence of dry powder coated films is similar, although much more reliant on nonsolvent forces to achieve a uniform film. According to Eq. (2) the time (t) required for two powder particles to coalesce is directly related to the viscosity of the powder coating (), the radius of the particles (R) and the surface tension of the coating () where k is a constant describing the process (Huang et al., 1997). From this equation it is clear that one must maintain low polymer viscosity to promote distribution of the material over the surface of the solid

3

Fig. 1. Schematic of film formation in dry powder coating systems.

substrate in order to yield an acceptable film. For thermoplastic powders, this will depend on the molecular weight of the polymers and on the curing temperature. Unlike many solvent-based systems, curing of dry powder coated products is nearly ubiquitous for both immediate release and controlled release systems to achieve a visually and functionally acceptable layer. The formulation must therefore be designed to obtained the desired characteristics and be produced in the minimal amount of time while still yielding a storage stable system. t=

kR 

time required for film coalescence in

dry powder coating

(2)

The melt viscosity–temperature relationship can be described by the Arrhenius equation, presented in Eq. (3), where A is a constant, E is the activation energy for viscous flow, R is the universal gas constant and T is the absolute temperature. Since viscosity decreases when temperature increases, higher processing and curing temperatures can be used to produce a higher quality film, even if degradation phenomena may also be accelerated:  = A eE/RT

Arrhenius equation describing polymer viscosity

as a function of temperature

(3)

In order to reduce the processing temperature of the powder coating and to shorten the curing phases, polymers which show excessively high Tg (>60 ◦ C) are combined with plasticizers able to decrease the Tg of the coating powders (Zheng et al., 2004; Sauer et al., 2007, 2009). Specific amounts of liquid or solid plasticizers can be added to the polymeric materials via physical mixture, concurrent addition during production or by the preparation of a solid dispersion coating formulation containing plasticizer prior to the coating operation. The nature of plasticizer addition will ultimately contribute to the type of coating process selected. Each of these approaches provides unique advantages and disadvantages, as summarized in Table 1. Alternatively, a polymeric solution containing the plasticizer can be spray dried so that a fine pre-plasticized polymeric powder can be obtained (Terebesi and Bodmeier, 2010). In general, powders having a particle size below 100 ␮m (Dv 50) have been demonstrated to be suitable for powder coating. Further consideration of

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

4

Table 1 Comparison of pre-processing techniques for dry powder coating. Technology

Advantage

Disadvantage

Liquid assisted

Use of conventional coating equipment Reduced liquid removal

Requires co-metering technology for feed addition Potential for heterogeneity of film components

Thermal adhesion

No requirements for co-metering No liquid removal

Requires pre-processing of feed powders Narrow temperature operation window

Electrostatic

Complex pattern coating

Need for specialized equipment

the coating to substrate particle size ratio is necessary to ensure appropriate adhesion and visual appearance. Examining the dry powder coating process as a whole, one notes a strong dependence on coating and substrate properties, as well as the interaction between the interfaces formed during the process. Successful implementation of dry powder coating technologies requires engineering of the product and process to carefully achieve the desired material attributes of the finished product. Each of the subsequent sections describes the application of these theoretical principles to the achievement of successful dry powder coatings.

Fig. 2. Schematic illustration of dry coating with a centrifugal granulator. Reproduced with permission from Obara et al. (1999).

3. Liquid assisted coating While conventional coating technologies rely on large volumes of solvent to ensure adhesion and the formation of a uniform coating, liquid assisted technologies limit the amount of liquid within the formulation. Additionally, this approach will often use a liquid phase excipient intended to remain in the drug product which will serve as an adhesive aid while providing some functionality for film formation. Since this approach is mechanistically different than conventional film coating technologies, theoretical aspects as well as technological considerations must be balanced to ensure success. 3.1. Processing equipment The first examples of dry coating processes by Obara et al. utilized the technology to apply enteric coatings onto pellets and tablets by layering hypromellose acetate succinate (HPMCAS, AQOAT® , Shin-Etsu) and co-spraying triethyl citrate (TEC) as the liquid plasticizer (Obara et al., 1999). The processes were performed using both a centrifugal granulator or fluidized bed for coating pellets and a perforated coating pan for coating tablets. Since these apparatuses are normally employed for solid oral dosage form unit operations, slight modifications were necessary. In addition to the liquid atomizers already in-place, these units were retro-fitted with powder feeders to support in-line addition of the dry powder coating. The dosing rate of the powders was monitored and controlled by loss-in-weight feeders, with feed streams entering directly into the processing chambers. Schematics of each apparatus are shown in Figs. 2–4. During processing, differential air flows and gravitational forces, in combination with simultaneous addition of the liquid plasticizer ensured adhesion of the powder to the substrate. Elevated temperatures within the processing chamber along with mechanical forces resulting from product bed movement further facilitated adhesion and film formation during the layering and curing processes. Pearnchob et al. reported on a series of experiments with dry powder coatings in which various polymeric powder mixtures containing either ethylcellulose, Eudragit® RS or shellac were layered onto drug containing pellets along with atomizing liquid

Fig. 3. Schematic illustration of dry coating with a top spray fluidized bed. Reproduced with permission from Obara et al. (1999).

plasticizers or emulsions of plasticizers with aqueous binder solutions. The presence of the liquid film on the surface of the cores increased the adhesion of the powders via capillary action while the use of the plasticizer reduced the temperature required for the softening and coalescence of the polymeric particles (Pearnchob and Bodmeier, 2003a,b,c). The coating was achieved employing a fluidized bed coater (GPCG 1, Wurster insert, Glatt® ) and loading the powders and the liquids through separate inlets. The pellets were cured in an oven at different times, temperatures and humidity values, which were shown to alter the rate of release. As curing and coalescence were more incomplete, more rapid dissolution was observed. Similar results were obtained more recently by Terebesi and Bodmeier employing a fluidized bed ball coater (Unilab 05 ball coater, Hüttling) which exploits the presence of two different nozzles by which liquid plasticizer and powder could be sprayed separately inside the coating chamber (Terebesi and Bodmeier, 2010). Kablitz et al. reported on dry coating processes for obtaining enteric coatings of pellets employing powder mixtures of HPMCAS and atomizing TEC, glycerol triacetated (triacetin) and acetylated monoglyceride (Myvacet 9-45K) mixtures as liquid plasticizers during processing (Kablitz et al., 2006, 2008; Kablitz and Urbanetz, 2009). The processes were carried out in a rotary fluid bed unit (GPCG 1.1, Glatt® ) with a three way nozzle immersed in the coating bed, as shown in Fig. 5. No special modification of the apparatus was required since it was originally designed for the preparation of pellets by drug powder layering and distributed the drug as powder onto inert cores while simultaneously spraying binder solutions (Vuppala et al., 1997; Gupta et al., 2001). The same equipment was used by Cerea et al. (2008a,b) for the layering of HPMCAS onto soft gelatin capsules.

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

5

Fig. 4. Schematic illustration of dry coating with a perforated pan tablet coating machine. Reproduced with permission from Obara et al. (1999).

3.2. Formulation case studies Liquid assisted dry powder coating requires the use of unique formulations in addition to the implementation of novel process designs. The compositions utilized are frequently characterized by a higher level of plasticizer, lower glass transition temperature and smaller particle size. Numerous examples have been published over the last two decades highlighting the design of liquid assisted dry powder coating. Several leading examples are discussed in detail within this section to illustrate the application of the technology. Particle size is a critical property of dry powder coatings. As mentioned previously, significant consideration of the coating material size is necessary to assure both uniformity of the final film and adhesion to the substrate. In a study by Obara et al., HPMCAS with a particle size of less than 10 ␮m was used as the model polymer and coated onto drug products containing pancreatin as the model active pharmaceutical ingredient (API). Using prior experience with aqueous based HPMCAS coatings, the polymer was pre-blended with talc prior to coating to enhance the surface smoothness of the coating and to prevent stickiness, as shown in Table 2. To increase the coating efficiency, TEC was mixed with acetylated monoglyceride (AMG) in a 3:2 ratio. AMG demonstrated good wettability of HPMCAS as shown by a low contact angle with the polymer. Another advantage of the use of AMG was the reduction of agglomeration that was observed for powder

coatings that contained only TEC as a plasticizer. The final TEC level in the coating formulation was 30% based on the dry polymer weight as shown in Table 2. During the coating process the outlet temperature was maintained at 42 ◦ C, allowing sufficient proximity to the glass transition temperature to supplement powder adherence achieved through capillary forces of the liquid plasticizer. This elevated temperature also aided in the coalescence process. Prior to the curing process at the completion of the coating process, water or an aqueous solution of hydroxypropyl methylcellulose (HPMC) was sprayed onto the coating bed to further facilitate film formation. The beads and tablets were then cured using heated air in a fluid bed or tablet coater until the exhaust temperature reached 50 ◦ C. Although the goal of developing an aqueous free coating process was not achieved since water was still required to facilitate film formation, the work demonstrated that solvent assisted coating was feasible while highlighting key formulation considerations for the technology (Obara et al., 1999). As substrate geometry changed so too did the formulation requirements. For smaller products liquid assisted dry powder coating was achieved without the need for subcoating, whereas larger products required the use of a HPMC subcoating. Although this difference in size related performance was not thoroughly investigated, the authors proposed multiple reasons for this behavior. These theories included: heterogeneous coating without a subcoat, poor adhesion without subcoat, and the prevention of surface damage during curing. The gastric resistance of the powder coated beads and tablets was assessed by dissolution and disintegration, respectively. As shown in Fig. 6, higher polymer levels were required to provide gastric resistance compared to beads and tablets that were coated using an aqueous process. The coating efficiency for the powder coating process was above 90% for all equipment variants used in the study and the processing time was approximately one-third of that for aqueous coating on the same scale. Upon storage at elevated temperature for up to 6 months the gastric resistance of the dry

Table 2 Formulation for dry powder coating.

Fig. 5. Schematic of a rotary fluid bed granulator: (1) rotor disc, (2) air slit, (3) pellet bed square view, (4) three way nozzle, and (5) powder feeder. Reproduced with permission from Kablitz et al. (2006).

Type

Ingredient

Partsa

Powder mixture

HPMCAS Talc

100 30

Liquid mixture (Plasticizer)

Triethyl citrate Acetylated monoglyceride

30 20

Reproduced with permission from Obara et al. (1999). a The amount of each ingredient is based on the weight of HPMCAS = 100.

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

ARTICLE IN PRESS

G Model IJP-13155; No. of Pages 15

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

6

Fig. 6. Gastric resistance of enteric coated beads (A) and enteric coated tablets (B). Reproduced with permission from Obara et al. (1999).

coated beads and tablets was comparable to ones prepared using an aqueous process. The HPMCAS-based powder coating process was further optimized by Kablitz et al. for the coating of pellets (Kablitz et al., 2006; Kablitz and Urbanetz, 2009). For processing, the researchers used a rotary fluid bed equipped with a three-way port nozzle to deliver polymer and plasticizer dispersion separately, but in close proximity to one another, into the coating bed. The influences of talc, colloidal silicon dioxide, TEC, and AMG on processability, coating efficiency, drug release, and physical stability were investigated. The coating formulations studied in this work are shown in Table 3. Theophylline was used as the model API. Experimental trials demonstrated that the presence of talc in the coating formulation reduced the gastric resistance of the coated pellets and decreased the coating efficiency of the process. The presence of talc in the coating formulation also delayed the drug release in pH 6.8 buffer. However, the absence of talc in the formulation resulted in agglomeration of the pellets upon storage. This behavior was attributed to the role talc played in the release and layering processes. Talc is commonly used as an anti-sticking agent, lubricating surfaces to aid in flow and minimize adhesion. This property reduced the sticking tendency of the product during manufacture, however, also inhibited the adherence of the dry coating powder onto the substrate. The less effective coating process most likely contributed to the poor gastric resistance observed (Kablitz and Urbanetz, 2009). As a result, colloidal silicon dioxide was used as an alternative anti-tacking agent. In contrast to talc, it was not premixed with the polymer prior to coating but applied as an overcoat following the coating process at a 1.4% level, based on the polymer weight. By not only changing the material type but also the addition sequence

Table 3 Composition of formulations prepared with HPMCAS, talc, colloidal silicon dioxide, TEC and AMG. Formulation

A

B

C

D

E

Powders HPMCAS (%) (%) Talc Colloidal silicon dioxide (%)

45–47 28 –

75 – –

74 – 1

75 – –

75 – –

Liquids TEC (%) Acetylated monoglyceride (%)

17.5–19 7.5–8

17.5 7.5

17.5 7.5

25 –

– 25

100

100

Total (%)

100

100

100

Reproduced with permission from Kablitz et al. (2006) and Kablitz and Urbanetz (2009).

it was possible to improve the coating process. Compared to the coating formulation proposed by Obara et al. the TEC/AMG ratio was increased. Trials confirmed that the addition of AMG reduced the contact angle of the plasticizer dispersion on the polymer and thus improved spreading of the plasticizer on the polymer. Formulations containing AMG alone or TEC/AMG mixtures were characterized with a higher coating efficiency and improved gastric resistance. Since coalescence is a necessary step in the film formation process, the inability of AMG to plasticize HPMCAS would drive incomplete film formation. As a result, formulations containing only AMG as a plasticizer did not provide sufficient gastric resistance. With dry powder coating operations, curing of the films is usually necessary to achieve complete and uniform coalescence. Zero order release kinetics were observed for the uncured pellets in acidic media. An enteric release profile was achieved for pellets with a 25% coating level that were cured at a product temperature of 53–55 ◦ C for 45 min. The physical stability of the theophylline pellets powder coated with HPMCAS was evaluated in a range of conditions. The powder coated pellets were stored at either 25 ◦ C/10% RH or 25 ◦ C/60% RH. Formulations containing only TEC as the plasticizer were characterized with the highest agglomeration tendency at 60% RH which was reflected in the loss of gastric resistance over time. The addition of AMG and colloidal silicon dioxide or talc reduced the agglomeration tendency of the formulations and facilitated constant gastric resistance properties over a storage time of up to 24 months at 10% RH and 60% RH. Samples stored at 40 ◦ C/75% RH agglomerated after 3 months and were not further evaluated. While maintaining stability in moderate temperature and humidity conditions, the failure of the drug product at accelerated storage conditions is a major challenge that faces many dry powder coated formulations. Due to the need to process at reasonable temperatures and impart sufficient mobility to the polymer to assure coalescence on a relevant time scale, it is necessary to reduce the glass transition temperature through formulation design. As a result, the stability performance under accelerated conditions can frequently become compromised. The role of AMG in the powder coating process was further evaluated using atomic force microscopy and DSC (Kablitz et al., 2008). The adhesion force between HPMCAS and HPMCAS containing AMG was shown to be higher compared to the force between HPMCAS and TEC containing substrates. According to DSC analysis, AMG is immiscible with HPMCAS and remained on the surface of the polymer. As a result, AMG forms liquid bridges and exerts capillary forces between HPMCAS particles thus improving efficiency of the process. Similar results were obtained for isopropyl myristate and isopropyl palmitate as wetting agents for HPMCAS (Klar and Urbanetz, 2009). This suggests that the design of dry powder coated

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

ARTICLE IN PRESS

G Model IJP-13155; No. of Pages 15

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx Table 4 Composition of formulations prepared with HPMCAS, talc, TEC and AMG. Formulation A

Formulation B

50.0% 30.0%

50.0% 30.0%

Liquids TEC AMG

12.5% 7.5%

20.0% –

100.0%

100.0%

Total

Table 5 Formulations for the coating of pellets with polymer powders in a fluidized bed coater. Formulation

Powders HPMCAS Talc

7

Composition (% w/w) Ethylcellulose

Powders Polymer Talc Total

Reproduced with permission from Cerea et al. (2008b).

Liquids Plasticizer 10% (w/w) HPMC solution

formulations must account for adhesion and film formation. It further indicates that the requirements for ideal adhesive aids and film forming additives will be different. Miscibility, an essential component for plasticization, may not be present for adhesive additives which provide better liquid bridging by forming immiscible liquids on the surface of the dry powders. Given this, careful consideration must be made in selecting formulation components for dry powder coating applications. Curing temperatures and times, in addition to formulation considerations, influence the quality of film formed. The influence of these conditions on film formation was studied using scanning electron microscopy and dissolution studies. Viscous flow, particle deformation, and the resulting dry sintering of the polymer particles are the main driving forces for film formation of powder coatings. The powder coated pellets were prepared using HPMCAS as model polymer and TEC/AMG mixtures as plasticizer and wetting agents. Following coating, the pellets were cured in a temperature controlled oven at temperatures ranging from 25 ◦ C to 95 ◦ C for up to 24 h. The glass transition temperature of the polymer/plasticizer mixture was identified as a critical parameter to optimize the curing conditions of a powder coated product. For a glass transition temperature of 51.7 ± 3.3 ◦ C, curing at 55 ◦ C for 45 min was determined to be the optimum curing conditions to obtain an enteric release profile. The results were based on visual observations using scanning electron microscopy and drug release studies, where poor quality was characterized by more rapid release and greater heterogeneity of the layer (Kablitz and Urbanetz, 2007). Results showed that lower curing temperatures required longer curing times, while higher temperatures resulted in agglomeration of the pellets. The HPMCAS based powder coating process was also adapted by Cerea et al. (2008b) for the coating of soft gelatin capsules. Under this approach, HPMCAS was pre-blended with talc prior to coating. TEC and a mixture of TEC and AMG were evaluated as plasticizing liquids and sprayed concurrently with the coating powder feed into the coating bed. The evaluated formulations are presented in Table 4. A rotary fluid bed with a three-way port nozzle was used for the powder coating of the capsules. The bed temperature was maintained at 40 ◦ C during the coating process. In order to overcome sticking during the early stages of the coating process, increased levels of talc and reduced liquid quantities were utilized. To maintain a similar TEC/polymer ratio, the TEC level was increased in the plasticizer mixture. During the initial phase of the coating process, only the plasticizer mixture was sprayed into the coating bed to prime the capsules surfaces and limit the loss of powder at the beginning of the process. Following the priming phase, the plasticizer mixture and polymer blend were delivered in parallel to the coating bed at a rate of 5 and 1.25 g/min, respectively. The coated capsules were then cured in the fluid bed at 38 ◦ C for 60 min. Coating levels of 22 mg/cm2 were shown to provide adequate gastric resistance. The coating efficiency of the process was 93% when TEC was pre-mixed with AMG and 87% for TEC alone as a plasticizer. As previously described by Obara et al., the improved process yield was attributed to the wetting of HMPCAS by AMG.

Total

Eudragit® RS PO

76.9 23.1

50.0 50.0

100.0

100.0

50.0–75.0 25.0–50.0 100.0

36.8–75.0 25.0–63.2 100.0

Reproduced with permission from Pearnchob and Bodmeier (2003a).

However, dissolution performance was comparable for both formulations and all capsules maintained their physical-technological and gastric resistance properties upon storage. Other adaptations of the liquid assisted powder coating process have been utilized for coating with Eudragit® RS PO and ethylcellulose (Pearnchob and Bodmeier, 2003a,b,c). Studies using propranolol HCl as the model drug utilized a fluid bed for the powder coating process. Coating powder and plasticizer were delivered separately into the bed, with product temperatures ranging from 34 ◦ C to 36 ◦ C for Eudragit® RS PO and from 45 to 47 ◦ C for ethylcellulose during the process. Following coating, the pellets were fluidized for 10 min and then cured in temperature controlled ovens. Different curing temperatures (40 ◦ C and 80 ◦ C) and durations (2–24 h) were evaluated for both polymers. Prior to coating Eudragit® RS PO was micronized to obtain a mean particle size of 9.4 ␮m. The average particle size of ethylcellulose and talc were 6.1 ␮m and 17.4 ␮m, respectively. Talc was used as anti-tacking agent and glidant to facilitate polymer powder flow into the coating bed. The studied formulations are listed in Table 5. Different plasticizers including TEC, acetyl tributyl citrate (ATC), and AMG were evaluated for the coating of pellets with Eudragit® RS PO and ethylcellulose. For each plasticizer three different levels based on the polymer weight (20%, 30%, and 40%) were investigated. Since spraying pure plasticizer resulted in agglomeration of the pellets, the plasticizers were diluted with a 10% aqueous HPMC solution. The level of plasticizer in the mixture ranged from 36.8 to 75.0% (w/w). The presence of more hydrophilic plasticizers such as TEC increased the drug release rate for both Eudragit® RS PO and ethylcellulose based coating formulations as shown in Fig. 7 for Eudragit® RS PO. Fig. 7 also demonstrates that the drug release rate decreased with increasing plasticizer level, which can be attributed to greater coalescence and enhanced film formation of the more mobile formulations. The drug release rate from pellets powder coated with Eudragit® RS PO and ethylcellulose was dependent on the curing conditions and decreased with increasing temperature and curing time as shown in Fig. 8 for pellets coated with ethylcellulose. Curing of the pellets that were powder coated with Eudragit® RS PO was necessary to improve the physical stability of the pellets upon storage. The drug release rate from Eudragit® RS PO coated pellets (40% AMG based on polymer weight) did not change upon storage for 3 years when the coated pellets were cured at 60 ◦ C for 2 h. In contrast, the drug release rate from uncured pellets was shown to significantly decrease over 3 years of storage at room temperature. This behavior was attributed to better distribution of the plasticizer and further coalescence of the polymer particles, resulting in the formation of denser films causing slower drug release rates. The physical stability of the ethylcellulose dry powder coated

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15 8

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

Fig. 7. Effect of plasticizer concentration on the propranolol HCl release from Eudragit® RS-coated pellets (curing at 60 ◦ C for 2 h, coating Levels 7.7–10.1%): (A) AMG, (B) acetyltributyl citrate, and (C) TEC. Reproduced with permission from Pearnchob and Bodmeier (2003b).

pellets was independent of curing conditions at room temperature over a 3-year period indicating no further coalescence of the polymer particles upon storage. It was also noted that powder coating processes generally require higher amounts for plasticizer compared to liquidbased coating applications to facilitate adequate film-formation. Although dry coating processes often require higher coating levels to obtain similar release profiles, the coating times were shown to be shorter compared to liquid-based processes as presented in Table 6. This brings about an important series of considerations around metrics used to justify manufacturing performance. Clearly, enhancements in processing time may provide significant improvements, which can factor into cost of goods analysis for drug product manufacturing. However, the added cost associated with greater quantities of material required for dry powder coating may prevent a realization of economic enhancements generally associated with the technology. As a result, careful consideration must be given to designing formulations that improve film formation and better match liquid coating based counterparts. In response to the need for greater formulation and process enhancement, further optimized coating processes have been proposed for pellets using ethylcellulose and Eudragit® RS. Using a fluid bed design with a liquid assisted concept, pellets were coated and cured for up to 24 h. The undiluted liquid plasticizer was sprayed

into the coating bed prior to the powder feed using a 1% (w/w) ratio based on the polymer weight. Eudragit® RS was micronized and preblended with talc in a 1:1 ratio prior to coating, while ethylcellulose was used without size reduction. Size reduction of the coating material provided benefits for adhesion as well as film formation during processing. Talc was included to reduce the sticking tendency. Different plasticizers were evaluated in the study including AMG and tributyl citrate. Prior to curing, colloidal silicon dioxide was applied to the pellet surface as an anti-sticking agent. Table 6 Coating time for the film coating of pellets with dry polymer powders or solvent based coatings. Coating formulation

Coating level (%)

Coating time (min)

®

Eudragit RS Dry powder coating Aqueous-based coating

Ethylcellulose Dry powder coating Aqueous-based coating Organic-based coating

15 20

31 41

15 20

128 171

20 5 5

30 44 111

Reproduced with permission from Pearnchob and Bodmeier (2003a).

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

9

Fig. 8. Effect of plasticizer concentration on the propranolol HCl release from ethylcellulose powder-coated pellets: (A) 40% AMG (coating level 30.3%), (B) 40% acetyltributyl citrate (coating level 18.1%), and (C) TEC (coating level 18.9%). Reproduced with permission from Pearnchob and Bodmeier (2003c).

HPMC E5 was included in the formulation and evaluated as a pore forming agent. Theophylline and chlorpheniramine maleate served as model drugs in the study. Higher coating levels of ethylcellulose were required for chlorpheniramine maleate pellets to control the drug release rate compared to the theophylline containing pellets. Tributyl citrate was shown to more effectively promote film formation than AMG for ethylcellulose. The incorporation of HPMC in the coating formulation increased the drug release rate. Smikalla et al. (2011) recommended the use of isopropyl myristate as a wetting and plasticizing agent for ethylcellulose powder coating applications. A fluid bed with rotor insert was used in the study. Coating powder and liquid plasticizer were separately fed into the coating bed. Following coating powder and plasticizer application, the pellets were mixed with colloidal silicon dioxide and cured in a temperature controlled oven at 80 ◦ C for up to 3 days. The study involved an extensive screening of organic cosolvents, plasticizers, surfactants, and lipids to optimize the coating efficiency for ethylcellulose. The contact angle of the plasticizer with the polymer was shown to be directly correlated with the coating efficiency (Fig. 9), which could be used as predictive tool for efficiency of the powder coating process. The application of liquid assisted coating technologies is a useful modality for quickly applying film coats. While time effective, additional formulation and process development is required to make the process more efficient from a material usage and performance perspective.

Fig. 9. Contact angles (n = 4) as a function of coating efficiency (n = 3). Reproduced with permission from Smikalla et al. (2011).

4. Thermal adhesion Operating in the extreme of liquid assisted processes, where the adhesive liquid level is minimized, one generally observes a greater dependence on the thermal characteristics of the coating powder. In fact, it becomes possible to remove the liquid aid altogether to rely solely on thermal adhesion of the coating powder. Due to the

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS

10

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

complex nature of the thermal adhesion mechanism in combination with the requirements for manufacturability and drug product stability, these formulations must be engineered to a greater degree than the liquid assisted systems. The following section describes the process equipment considerations and formulation aspects that are essential for designing dry powder coating systems based on thermal adhesion. 4.1. Processing equipment considerations When compared to liquid assisted dry powder coating, thermal adhesion methods have received less attention, although they too have traditionally relied on adaptation of existing manufacturing equipment to support production. Several of the most common adaptations have largely been centered around spheronizers and rotary fluid beds. For these processes, the substrate is maintained at a temperature that facilitates softening and spreading of the coating powder. This is further aided by mechanical forces of the process which work to compact powders on the surface of the substrate. It is also critical that the temperature is maintained below the critical threshold for agglomeration of the powder and drug product. Given the narrow operating window for processing, it is imperative to maintain a high accuracy of process control during manufacture. One technique extensively reported in the literature has been the adaptation of a spheronizer to the production of dry powder coated drug product (Cerea et al., 2004; Zheng et al., 2004; Sauer et al., 2007). This process involved only solid materials using a laboratory scale spheronizer (Model 120, G.B. Caleva; Dorset, UK) with a smooth stainless steel disc. Represented in Fig. 10, the edges of the disk were tilted at a 45◦ angle to facilitate the tumbling movement of the tablets and to prevent the loss of the coating powders. A batch size of 50 g of tablets was employed for each process. The heat necessary to perform the powder coating was generated by an infrared lamp positioned 3 cm above the top of the spheronization chamber (250 W Infrared Red Heat Bulb, General Electric, USA). The temperature of the coating chamber was controlled by adjusting the power of the lamp with a variable transformer (TYPE PF1010, Staco, Inc., Dayton, OH, USA). The temperature of the coating bed was constantly monitored with a digital thermoprobe. The powders were distributed at a constant rate on the top of the rotating tablets using a single screw powder feeder. To prevent the heat loss during the process the spheronizer chamber was closed by a glass cover.

Fig. 10. Schematic representation of the laboratory scale spheronizer used for the thermal coating process: (1) rotating disk; (2) infrared lamp; (3) powder feeder; (4) temperature probe; (5) coating cores; and (6) glass cover. Reproduced with permission from Cerea et al. (2004).

The temperature control was the most critical parameter during the powder coating. Due to the small scale of the equipment and to the low amount of cores involved, coating trials that employed forced hot air as the heating source were unsuccessful. With this technique poor quality coatings having reduced yields resulted. Curing of the powdered tablets was performed in either the spheronizer or in a static oven on Teflon® plates. This application is of critical importance because most of the formulations used will not have sufficient time to coalesce. Engineering of powder physico-mechanical properties is often necessary to achieve necessary performance. In this particular study, the tablets were cured in a static oven after powder layering at 80 ◦ C for 12 h to complete film formation. SEM analysis of cross-sectioned coated tablets before and after curing illustrated the efficiency of the curing conditions (Fig. 11). In particular, photomicrographs of the uncured coated tablets revealed a thick, porous layer, with polymer particles visible along the entire cross-section of the coating. Moreover, the thickness of the layer is appreciably different depending on position, with a thinner coating on the edge of the tablets. On the contrary, samples cured for 12 h at 80 ◦ C produced more homogeneous coatings with compact and continuous film layers. The polymer particles melted into uniform films of constant thickness on the surface of the tablet. Small-scale simulation of the curing process can be achieved using adaptations of film casting methodologies. For these studies, powder is layered onto substrate sheets and heated to simulate the process (Cerea et al., 2004). It is also theoretically possible to incorporate pressure cycles to the powder to mimic the effects of mechanical agitation in the bed. In this study, powder cast Eudragit® E PO films were used to optimize the curing conditions. Criteria for adequate film formation were film transparency, film thickness, and morphology. Coating levels of 7 mg/cm2 , 10 mg/cm2 , and 14 mg/cm2 of Eudragit® E PO/talc mixtures successfully delayed the drug release in pH 5.5 and pH 6.8 buffers, as required for taste masking applications. Using this approach an immediate release of theophylline was observed in pH 1.0 hydrochloric acid for all investigated coating levels. The coating additives PVP K-90, glycerol monostearate, and polyethylene glycol 3350 increased the drug release rate from the powder coated tablets. HPMC K4M also shortened the onset of drug release in pH 6.8 buffer, however, slightly increased the lag time in pH 1.0 hydrochloric acid. Process considerations will also need to be given for the materials themselves. Many powders will require specific sizes which are often in the micron scale. Milling techniques will play a critical role and have already been discussed within the liquid assisted concept. Further consideration of the nature of the powder is also necessary. In many cases it will be necessary to combine the polymer, plasticizer and opacifier. This mixture will still need to maintain flowability and dispersibility while also being of a suitable particle size. Solid dispersion technology can be used to quickly and effectively prepare complex powder particles of the desired size. The most commonly reported techniques for this are spray drying and hot-melt extrusion. In a recent case study (Terebesi and Bodmeier), two different grades of ethylcellulose (7 cP and 10 cP) were pre-plasticized with 20% (w/w) (based on the polymer) medium chain triglycerides (MCT) by premixing the polymer with MCT followed by hot-melt extrusion and cryogenic grinding. This allowed for the production of a fine dense powder coating material having the necessary thermal characteristics to support manufacturing. Alternatively, commercially available aqueous ethylcellulose dispersions (Aquacoat® , Surelease® ) was spray-dried. Prior to spray-drying, the Aquacoat® and MCT (20%, w/w based on the polymer) were mixed for 24 h to equilibrate the plasticizer distribution in the mixture. Surelease® was spray-dried

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

11

Fig. 11. Scanning electron micrographs of Eudragit® E PO powder coated tablets (14 mg/cm2 ). Cross-sections of uncured tablet (A and C) and tablet cured for 12 h at 80 ◦ C (B and D). Reproduced with permission from Cerea et al. (2004).

after dilution with deionized water to yield a fine powder suitable for dry powder coating. Terebesi and Bodmeier noted that filmformation was improved for the spray-dried material compared to the hot-melt extruded coating powder. The difference in film formation was attributed to the difference in mean particle size of the hot-melt extrudate compared to the spray-dried material, further highlighting the importance of dry powder engineering and particle sizing. 4.2. Formulation case studies Dry powder coating formulations are engineered to provide the necessary thermal characteristics. Compositionally, this is achieved through the incorporation of polymer, plasticizer, opacifier, colorant and anti-sticking agent. Unlike traditional formulations, higher levels of plasticizers are required to ensure adhesion and film formation. The pre-plasticization process was adapted by Terebesi and Bodmeier for the controlled release polymer ethylcellulose. Anti-sticking agents are also a necessity in coating formulations to prevent adhesion during processing. Even though the amount of anti-sticking agent inside the powder coating formulation has never been extensively investigated, the presence of 10% of talc in the powder coating blends has been considered successful by researchers in the field for preventing the agglomeration of the powder particles during storage and during the distribution of the powders on the cores. Trials performed using powders without talc resulted in excessive adhesion of the powders on the surface of the tablets with irregular thickness of the layer (Cerea et al., 2004). The application of an additional overcoating layer of 2% of talc after the curing step eliminated the tackiness of the coated tablets when the final coating film had a Tg value of the pre-plasticized polymer around 40 ◦ C (Sauer et al., 2007, 2009).

The colorants, together with opacifiers, are materials that are commonly used in all formulations intended for film coating for their esthetic contribution to the final product. The colors enhance the image of the product making it easier for market promotion and identification of the product both by the patient and during packaging operations. At the same time the use of dyes in the coating layer can help to improve the stability of the active ingredient by protecting it from light degradation. For aqueous film coating, water-insoluble colorants (pigments and lacquers) are preferred over soluble dyes due to the fact that during the drying step the solvent tends to migrate to the surface bringing the soluble dye molecules with it. In the dry powder coating, since no liquids are involved and the process does not include a drying phase, no migration of the colorant is expected. The level of plasticizer becomes a critical aspect of successful formulation that strongly impacts performance. At a bed temperature of 55–60 ◦ C successful coating of tablets with Eudragit® E PO was achieved, whereas processing below the glass transition temperature of the polymer did not result in sufficient polymer adhesion (Cerea et al., 2004). In contrast, coating temperatures above 70 ◦ C caused irregular polymer layering due to adherence and physical deformation. The addition of low-melting excipients including glycerol monostearate and polyethylene glycol 3350 was shown to improve coating powder adhesion, highlighting how plasticizing materials could be used to enhance performance. A modified lab-scale spheronizer was also used by Zheng et al. for the powder coating of tablets with the acrylic polymers Eudragit® RS and RL PO with theophylline serving as the model compound. Eudragit® RS/RL PO (95:5) mixtures were pre-plasticized with TEC using a hot-melt extrusion process. Pre-plasticization of the polymer eliminated the need of the separate spray of a plasticizer solution. The extrudate was then cryogenically ground and blended with talc in a 10% ratio based on the weight of the

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15 12

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

Fig. 12. Dissolution stability testing of theophylline tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC at 25 ◦ C/60% RH (A) and 40 ◦ C/75% RH (B), Using the USP 27 apparatus 2 and 900 mL of 50 mM pH 7.4 phosphate buffer at 37 ◦ C and 50 rpm. : initial; : 1 month; : 3 months. Reproduced with permission from Zheng et al. (2004).

polymer. The investigated TEC levels ranged from 5 to 15% based on the polymer weight. The coating bed temperature was adjusted based on the plasticizer level and ranged from 55 ◦ C to 60 ◦ C for 15% triethyl citrate and 80 ◦ C to 85 ◦ C for 0% triethyl citrate. The powder feed rate was set to 0.5 g/min. Prior to powder coating, the tablets were primed with a low-melting excipient to facilitate the coating powder adhesion. Polyethylene glycol, poloxamer 407, and cetyl alcohol were evaluated as priming agents. Cetyl alcohol was selected as the most appropriate primer for Eudragit® RS/RL mixtures based on its hydrophobicity. Following the coating powder application, the tablets were cured in an oven at 80 ◦ C for up to 24 h to complete the film formation process. The drug release rate from Eudragit® RS/RL coated tablets was dependent on the TEC level and decreased with increasing plasticizer level, which suggested greater coalescence of the film. At the 5% TEC level a coating level of 5% Eudragit® RS/RL resulted in a lag time of about 2 h followed by a sustained release over 10 h, demonstrating that powder coating is an efficient method to control the drug release rate. The physical stability of the powder coated tablets was also evaluated using dissolution testing. The tablets were stored in induction sealed HDPE bottles at 25 ◦ C/60%RH and 40 ◦ C/75%RH over a period of 3 months. As shown in Fig. 12, no significant decrease in drug release rate was observed for the investigated storage conditions indicating excellent physical stability of the coated dosage forms. Similar studies have also shown the application of spheronizers for the coating of tablets with Eudragit® L 100-55 (Sauer et al., 2007; Sauer and McGinity, 2009b). Prior to coating, Eudragit® L 100-55 was pre-plasticized with up to 40% (w/w) TEC based on the polymer weight using a similar process as proposed by Zheng et al. Increasing TEC levels were shown to reduce the glass transition temperature, melt viscosity and spreading coefficient of the polymer. Talc was used as anti-tack agent to prevent agglomeration of the tablets during coating powder application and added in a 10% ratio to the ground polymer powder. PEG 3350 was used as low-melting hydrophilic wetting agent to promote coating powder adhesion and was used both as primer and component of the coating powder. The authors demonstrated that PEG 3350 was miscible with Eudragit® L 100-55, reducing the glass transition temperature and the melt viscosity of the polymer (Sauer and McGinity, 2009a). Following coating, the tablets were cured on Teflon trays at 60 ◦ C for 24 h and overcoated with 2% (w/w) talc based on the weight of the coated tablets. Alternatively, coating can be achieved in the spheronizer itself, based on the properties of the formulation. In another example, chlorpheniramine maleate was used as a model compound within tablets that were dry powder coated and cured at 60 ◦ C for 2 h in a spheronizer (Sauer et al., 2007). The influence of TEC content and coating level on the release from powder coated tablets was evaluated and the results are summarized in Fig. 13. Higher plasticizer levels were shown to enhance film formation and to

decrease the drug release rates both in 0.1 N hydrochloric acid and pH 6.8 buffer. Unlike aqueous coating, powder coating minimized partitioning of the drug into the film coating during the coating process. Physical stability of the powder-coated chlorpheniramine

Fig. 13. Influence of TEC content and coating level on the release of chlorpheniramine maleate from tablets powder-coated with pre-plasticized Eudragit® L 100-55 using USP apparatus 2. Dissolution in 900 mL 0.1 N HCl for 2 h followed by 4 h in 900 mL, pH 6.8 buffer. , 7% polymer weight gain. , 10% polymer weight gain. , 15% polymer weight gain. (A) 20% TEC based on the polymer weight. (B) 30% TEC based on the polymer weight. (C) 40% based on the polymer weight. Reproduced with permission from Sauer et al. (2007).

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

tablets was confirmed at 25 ◦ C/60% RH over a storage time of 12 weeks. Subcoating can also be used to influence the performance of the manufacturing process and the quality of the coats (Sauer et al., 2007, 2009). Subcoats of Eudragit® E PO and Eudragit® RL PO were evaluated in combination with the enteric polymer Eudragit® L 100-55 for the powder coating of tablets. HPMC K4M and PEG 3350 were added to the subcoat formulations to increase water influx and dissolution rate in the buffer stage of the enteric test. The pore formers were used at a 10% (w/w) ratio based on the polymer weight in the subcoat formulations. Similar to previous studies, Eudragit® RL PO and Eudragit® L 100-55 were both preplasticized prior to coating powder application. Talc was added at 10% (w/w) level as anti-tack agent. The application of the Eudragit® E PO or Eudragit® RL subcoat were shown to assist with adhesion of the enteric polymer Eudragit® L 100-55 and reduce the amount of enteric polymer required for enteric protection. Using a combination of formulation designs it is possible to alter the adhesion, surface spreading and mobility of the coating powders, leading to greater coalescence and enhanced film formation. While thermal adhesion methods may not currently be preferred in industry, the flexibility for formulation design through solid dispersion engineering and the parallel development of enhanced manufacturing technologies will hopefully translate into greater use of the technology in the future.

5. Electrostatic coating Electrostatic powder coatings are commonly used in the metal finishing industry, coating everything from metal bolts to automobiles. The process involves the deposition of charged coating powder onto a grounded substrate (Luo et al., 2008). While this technique has seen the lowest level of publication for any of the dry

13

powder techniques, it has also been shown to be the most advanced in terms of commercial application. Application of the technology within the pharmaceutical industry has demonstrated that more intricate patterns can be formed on the coating for brand identification purposes while also providing comparable production outputs to larger commercial units. 5.1. Process equipment considerations Requiring specialized equipment, Phoqus Pharmaceuticals, Ltd. developed an electrostatic powder coating process for tablets (Hogan et al., 2006). In this system they utilized a custom engineered coating apparatus to coat both sides of the tablet cores separately. Infrared radiation was applied for a short amount of time to facilitate film formation of Eudragit® RS coatings. The technology known as LeQtracoat® exploited the electrostatic attraction between oppositely charged materials to promote the adhesion of the coating powders onto the surface of tablets (Fig. 14). With the same principle as the ink toner deposition in electrophotography (photocopying) the tablets were coated individually one side at a time in special manufacturing plants with capacity up to 250,000 units/h. With this technique, the coating material was directed with such precision that 3D images could be created. Final curing leading to film formation could also be achieved within the same apparatus, allowing for similar performance to conventional coating operations. Qiao et al. (2010a) developed a powder coating process that combined electrostatic powder coating technology with a traditional liquid pan coating technique for the powder coating of tablets. The pan coater was equipped with a liquid spray nozzle, an electrostatic spray gun, and a powder feeder. Ibuprofen was used a model drug for the study. The polymers Opadry® AMB (polyvinyl alcohol based coating blend) and Eudragit® E PO were evaluated. Prior to coating, the polymer powders were ground to

Fig. 14. Schematic diagram of the electrostatic dry powder coating process.

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15 14

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

an average particle size of 26.6 ␮m and 10.0 ␮m for Opadry® AMB and Eudragit® E PO, respectively. The coating process consisted of the following steps: pre-heating, plasticizer spraying, feeding of the charged particles into the coating bed, and curing at elevated temperature. Polyethylene glycol 400 and glycerol/water mixtures (1:1, v/v) were used as plasticizer. In addition to lowering the glass transition temperature, the plasticizer layer promoted powder adhesion by capillary forces and reduction of the electrical resistivity of the core tablets. The polymer particles were negatively charged using an electrostatic spray gun and followed the direction of the electrical field between tip of the spray gun and grounded coating pan. The repulsive forces between the polymer particles promoted the dispersion of the coating powder. The coating level was dependent on the charging voltage used to spray the coating powder. Film formation of the described coating process occurred during curing at 40–60 ◦ C for 2 h based on visual observation using scanning electron microscopy. By achieving a charge on the powder it was possible to coat a drug product using this electrostatic – liquid assisted hybrid methodology. Such combinations of technologies provide benefits for more effective film formation and may also represent the next steps for applying this technology more broadly throughout the industry. 5.2. Formulation considerations Compositionally, it is critical that charge can be induced into the powder constituents. Similar to the other methodologies, adherence and film formation are critical aspects of formulation design. While these are not handled in a fundamentally different way from the previous discussion, the example below is provided to illustrate the strategy for formulation design of electrostatic powder coatings. The electrostatic pan coating process was also evaluated for the sustained release polymers Eudragit® RS and RL (Qiao et al., 2010b). Ibuprofen was used as model drug for the study, TEC was the plasticizer and talc was used as anti-tack agent in the formulation. Eudragit® RS and RL as well as talc were milled prior to coating and the average particle size was 18.4 ␮m, 16.5 ␮m, and 28.9 ␮m, respectively. Again, the tablets were pre-heated prior to coating. Following the spray of the plasticizer, the coating powder was sprayed into the tablet bed. The coating powder consisted of 50% (w/w) Eudragit® RS/RL mixtures, 49% talc, and 1% of pigment. As shown previously, the resistivity of the tablets was reduced with the application of the liquid plasticizer. Curing for at 50 ◦ C and 60 ◦ C 2 h was required to facilitate film formation. Tablets that were cured at lower temperatures were characterized with incomplete film formation based on visual observation using scanning electron microscopy. Curing of the powder coated tablets also affected the drug release rate. Higher curing temperatures and longer curing times were shown to decrease the drug release rate pH 7.2 phosphate buffer. The authors were able to control the drug release rate by adjusting the Eudragit® RS/Eudragit® RL ratio in the coating powder. 6. Current trends and future directions Dry powder coating technology for pharmaceutical applications has developed considerably over the last decade, however is still significantly behind other industries in terms of technological application. At present, dry powder coating technology has been able to differentiate itself from the solvent-based counterparts, however, the need for additional development and customized equipment has limited its use in commercial applications. Benefits for costs of goods, throughputs and manufacturing efficiencies

that have been gained in other industries have yet to materialize for the pharmaceutical sector, leading to a much slower adoption of the technology. On the horizon, however, one notes several major trends which may help to drive the industry closer to large scale adoption of dry powder coating technologies for oral delivery. First, the current changes in global austerity have pushed many pharmaceutical and biotechnology companies to seriously examine manufacturing costs. The lower cost associated with dry powder coating technology makes it attractive for both brand and generic companies seeking to reduce operating expenses. Another major driver in the future will be the needs of advanced drug products, specifically focused in the area of counterfeit resistance and amorphous formulation support. Counterfeit drugs are a major problem facing global pharmaceutical companies, with steps being taken to protect the supply chain and also develop visually differentiated products. Dry powder coating, particularly electrostatic dry powder coating, can be used to prepare novel identifying marks onto drug products in a rapid cost effective manner leading to enhanced brand identification. Beyond this, the potential to eliminate the need for solvents allows for more effective application of coatings to moisture sensitive products. This opens up unique opportunities in the drug product design of amorphous systems and may potentially play a role in future product designs. Given the potential of the technology, academic research will continue in earnest as the pharmaceutical industry continues the adoption of the technology. Over time and driven by a number of different factors, dry powder coating appears poised to become a major pharmaceutical coating technology in the future. References Bose, S., Bogner, R., 2007. Solventless pharmaceutical coating processes: a review. Pharm. Dev. Technol. 12, 115–131. Cerea, M., Zheng, W., Young, C.R., McGinity, J.W., 2004. A novel powder coating process for attaining taste masking and moisture protective films applied to tablets. Int. J. Pharm. 279 (1–2), 127–139. Cerea, M., Zema, L., Palugan, L., Gazzaniga, A., 2008a. Recent developments in dry coating. Pharm. Technol. Eur. 2, 40–44. Cerea, M., Foppoli, A., Maroni, A., Palugan, L., Zema, L., Sangalli, M.E., 2008b. Dry coating of soft gelatin capsules with HPMCAS. Drug Dev. Ind. Pharm. 34 (11), 1196–1200. Gordon, M., Taylor, J.S., 1952. Ideal copolymers and the second-order transitions of synthetic rubbers. i. non-crystalline copolymers. J. Appl. Chem. 2 (9), 493–500. Grundke, K., Uhlmann, P., Gietzelt, Th., Redlich, B., Jacobasch, H.-J., 1996. Studies on the wetting behaviour of polymer melts on solid surfaces using the Wilhelmy balance method. Colloids Surf., A 116, 93–104, - S. Gupta, V.K., Beckert, T.E., Price, J.C., 2001. A novel pH- and time-based multi-unit potential colonic drug delivery system. I. Development. Int. J. Pharm. 213, 83–91. Hogan, J.E., Page, T., Reeves, L., Staniforth, J.N., 2006. Powder coating composition for electrostatic coating of pharmaceutical substrates. US Patent 7,008,668. Huang, Z., Scriven, L.E., Davis, H.T., Eklund, W.E., 1997. Film formation in powder coatings. In: Abstracts of the Waterborne, Higher-Solids and Powder Coatings Symposium, New Orleans, LA, February 5–7, 1997, pp. 328–341. ´ I., Dreu, R., Burjak, M., Homar, M., Kerˇc, Srˇciˇc, S., 2009. Microparticle size control Ilic, and glimepiride microencapsulation using spray congealing technology. Int. J. Pharm. 381 (2), 176–183. Kablitz, C.D., Urbanetz, N.A., 2009. Stability of dry coated solid dosage forms. Pharm. Dev. Technol. 14 (6), 613–622. Kablitz, C.D., Urbanetz, N.A., 2007. Characterization of the film formation of the dry coating process. Eur. J. Pharm. Biopharm. 67 (2), 449–457. Kablitz, C.D., Harder, K., Urbanetz, N.A., 2006. Dry coating in a rotary fluid bed. Eur. J. Pharm. Sci. 27, 212–219. Kablitz, C.D., Kappl, M., Urbanetz, N.A., 2008. Parameters influencing polymer. particle layering of the dry coating process. Eur. J. Pharm. Biopharm. 69 (2), 760–768. Klar, F., Urbanetz, N.A., 2009. The role of capillary force promoters in dry coating procedures – Evaluation of acetylated monoglycerides, isopropyl myristate and palmitate. Eur. J. Pharm. Biopharm. 71 (1), 124–129. Lo, J.E., Appeal, L.E., Herbig, S.M., McCray, S.B., Thombre, A.G., 2009. Formulation design and pharmaceutical development of a novel controlled release form of azithromycin for single-dose therapy. Drug Dev. Ind. Pharm. 35 (12), 1522–1529. Luo, Y., Zhu, Ma, Y., Zhang, H., 2008. Dry coating, a novel coating technology for solid pharmaceutical dosage forms. Int. J. Pharm. 358, 16–22. Obara, S., Maruyama, N., Nishiyama, Y., Kokubo, H., 1999. Dry coating: an innovative enteric coating method using a cellulose derivative. Eur. J. Pharm. Biopharm. 47 (1), 51–59.

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),

G Model IJP-13155; No. of Pages 15

ARTICLE IN PRESS D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

Pearnchob, N., Bodmeier, R., 2003a. Dry polymer powder coating and comparison with conventional liquid-based coatings for Eudragit® RS, ethylcellulose and shellac. Eur. J. Pharm. Biopharm. 56 (3), 363–369. Pearnchob, N., Bodmeier, R., 2003b. Dry powder coating of pellets with micronized Eudragit® RS for extended drug release. Pharm. Res. 20 (12), 1970–1976. Pearnchob, N., Bodmeier, R., 2003c. Coating of pellets with micronized ethylcellulose particles by a dry powder coating technique. Int. J. Pharm. 268 (1–2), 1–11. Qiao, M., Zhang, L., Ma, Y., Zhu, J., Chow, K., 2010a. A novel electrostatic dry powder coating process for pharmaceutical dosage forms: immediate release coatings for tablets. Eur. J. Pharm. Biopharm. 76 (2), 304–310. Qiao, M., Luo, Y., Zhang, L., Ma, Y., Stephenson, T.S., Zhu, J., 2010b. Sustained release coating of tablets with Eudragit® RS/RL using a novel electrostatic dry powder coating process. Int. J. Pharm. 399 (1–2), 37–43. Sauer, D., McGinity, J.W., 2009a. Influence of additives on melt viscosity, surface tension, and film formation of dry powder coatings. Drug Dev. Ind. Pharm. 35 (6), 646–654. Sauer, D., McGinity, J.W., 2009b. Properties of theophylline tablets dry powder coated with Eudragit® E PO and Eudragit® L 100-55. Drug Dev. Technol. 14 (6), 632–641.

15

Sauer, D., Zheng, W., Coots, L.B., McGinity, J.W., 2007. Influence of processing parameters and formulation factors on the drug release from tablets powder-coated with Eudragit® L 100-55. Eur. J. Pharm. Biopharm. 67 (2), 464–475. Sauer, D., Watts, A.B., Coots, L.B., Zheng, W., McGinity, J.W., 2009. Influence of polymeric subcoats on the drug release properties of tablets powder-coated with pre-plasticized Eudragit® L 100-55. Int. J. Pharm. 367 (1–2), 20–28. Smikalla, M., Mescher, A., Walzel, P., Urbanetz, N.A., 2011. Impact of excipients on coating efficiency in dry powder coating. Int. J. Pharm. 405 (1–2), 122–131. Terebesi, I., Bodmeier, R., 2010. Optimized process and formulation conditions for extended release dry polymer powder-coated pellets. Eur. J. Pharm. Biopharm. 75, 63–70. Vuppala, M.K., Parikh, D.M., Bhagat, H.R., 1997. Application of powder- layering technology and film coating for manufacture of sustained-release pellets using a rotary fluid bed processor. Drug Dev. Ind. Pharm. 23 (7), 687–694. Zheng, W., Cerea, M., Sauer, D., McGinity, J.W., 2004. Properties of theophylline tablets powder-coated with methacrylate ester copolymers. J. Drug Deliv. Sci. Technol. 14 (4), 319–325.

Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut http://dx.doi.org/10.1016/j.ijpharm.2013.02.032

(2013),