Extrusion and spheronization in the development of oral controlled-release dosage forms

reviews

research focus

PSTT Vol. 2, No. 4 April 1999

Extrusion and spheronization in the development of oral controlled-release dosage forms Rajesh Gandhi, Chaman Lal Kaul and Ramesh Panchagnula The concept of multiparticulate dosage forms was introduced in the 1950s. With the increasing use of multiparticulate controlled release (CR) oral dosage forms, in recent times there has been a rise in interest in the methods of preparing these dosage forms. A method that has gained increased usage over the past few years is that of extrusion and spheronization. It has been extensively explored as a potential technique and also as a future method of choice for preparation of multiparticulate CR dosage forms. In this review an attempt is made to outline the general process of extrusion and spheronization and to assess its importance in the development of multiparticulate CR oral dosage forms.

Rajesh Gandhi, Chaman Lal Kaul and Ramesh Panchagnula* Department of Pharmaceutics National Institute of Pharmaceutical Education and Research Sector 67, S.A.S. Nagar Punjab 160 062 India *tel: 191 172 673848 fax: 191 172 677185 e-mail: [email protected]

160

▼ Conventional medication systems that require multi-dose therapy are not without problems. With a view to overcoming these problems, the current trend in pharmaceutical research is to design and develop new formulations, thereby enhancing the therapeutic efficacy of existing drugs. Moreover, the impetus for research into drug delivery can be attributed to the exorbitant cost and large development period involved in ‘new drug development’ with concomitant recognition of the therapeutic advantages of controlled drug delivery. Controlled release (CR) technology has rapidly emerged over the past three decades as a new interdisciplinary science that offers novel approaches to the delivery of bioactive agents into systemic circulation at a predetermined rate. The choice of drug to be delivered, clinical needs, and drug pharmacokinetics are some of the important considerations in the development of CR formulations, in addition to the relationship be-

tween the rate of drug release from the delivery system to the maximum achievable rate of drug absorption into the systemic circulation. By achieving a predictable and reproducible bioactive agent release rate for an extended period of time, CR formulation can achieve optimum therapeutic responses, prolonged efficacy, and also decreased toxicity1. The therapeutic advantages of CR systems over conventional dosage forms have been amply documented in the literature2,3. One of the important advantages is the reduced dosing frequency, thereby improving patient compliance and therapeutic efficacy. In addition, the constant blood levels of the drug, unlike in conventional dosage forms, leads to a minimization of drugrelated side effects. Although a variety of dosage forms have been developed for the preparation of oral CR formulations, they broadly fall into two categories: single unit dosage forms and multiple (multiparticulate) dosage forms. Single unit dosage forms Single unit dosage forms are defined as oral dosage forms that consist of single units, with each unit containing one dose of the drug and intended to be administered singularly. There are several such dosage forms that have been developed for the CR of various bioactive materials, as has been reported in the literature and of which monolithic matrix-based tablets are the most common single unit dosage form used for controlled drug delivery4,5. Advantages associated with such dosage forms include high drug loading, simple and cost-effective manufacturing operations, the availability of a wide range of excipients and polymers for controlling drug release

1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00136-4

research focus

PSTT Vol. 2, No. 4 April 1999

and the possibility of using different mechanisms for drug release control (such as diffusion controlled, swelling controlled, erosion controlled or a combination of all of these). Single unit dosage forms that have been used for controlled drug delivery include drug-release controlling polymer membrane-coated tablets and osmogen-controlled formulations6,7. Multiple unit dosage forms The concept of the multiple unit dosage form was initially introduced in the early 1950s. These forms play a major role in the design of solid dosage form processes because of their unique properties and the flexibility found in their manufacture. These forms can be defined as oral dosage forms consisting of a multiplicity of small discrete units, each exhibiting some desired characteristics.Together, these characteristic units provide the overall desired CR of the dose.These multiple units are also referred to as pellets, spherical granules or spheroids. Pellets or spherical granules are produced by agglomerating fine powders with a binder solution. These pellets usually range in size from 0.5–1.5 mm and in some applications may be as large as 3.0 mm (Ref. 8). The use of pellets as a vehicle for drug delivery at a controlled rate has recently received significant attention. Applications are found not only in the pharmaceutical industry but also in the agribusiness (such as in fertilizer and fish food) and in the polymer industry9. There are numerous advantages offered by multiple unit dosage forms.

• • • • • •

Pellets disperse freely in the gastrointestinal (GI) tract, and so they invariably maximize drug absorption, reduce peak plasma fluctuation, and minimize potential side effects without appreciably lowering drug bioavailability10. Pellets also reduce variations in gastric emptying rates and overall transit times.Thus inter- and intra-subject variability of plasma profiles, which is common with single unit regimens, is minimized11. High local concentration of bioactive agents, which may inherently be irritative or anesthetic, can be avoided12. When formulated as modified-release dosage forms, pellets are less susceptible to dose dumping than the reservoir-type, single unit formulations12. Better flow properties, narrow particle size distribution, less friable dosage form and uniform packing13,14. The pellets offer advantages to the manufacturer because they provide an ideal shape [low surface area to volume ratio] for the application of film coating. They can also be made attractive because of the various shades of colour that can be easily imparted to them during the manufacturing process, thus enhancing the product elegance and organoleptic properties12.

•

reviews

Pellets also offer the advantage of flexibility for further modifications, such as compression to form tablets or coating to achieve the desired dosage-form characteristics15.

Methods of pellet preparation Pellets are spheres of varying diameter and they may be manufactured by using different methods according to the application and the choice of producer. In a spray-drying process, aqueous solution of core materials and hot solution of polymer is atomized into hot air, the water then evaporates and the dry solid is separated in the form of pellets, usually by air suspension. In general, a spray-drying process produces hollow pellets if the liquid evaporates at a rate faster than the diffusion of the dissolved substances back into the droplet interior or if due to capillary action dissolved substances migrate out with the liquid to the droplet surface, leaving behind a void12,16. In spray congealing a slurry of drug material that is insoluble in a molten mass is spray congealed to obtain discrete particles of the insoluble materials coated with congealed substances. A critical requirement for this process is that the substance should have a well-defined melting point or small melting zone12. In fluidized bed technology a dry drug form is suspended in a stream of hot air to form a constantly agitated fluidized bed. An amount of binder or granulating liquid is then introduced in a finely dispersed form to cause a momentary reaction prior to vaporization.This causes the ingredients to react to a limited extent, thereby forming pellets of active components. Using this process Govender and Dangor13 and Mathir et al.17 prepared and characterized pellets of Salbutamol and Chlorpheniramine maleate, respectively. In the rotary processor (rotogranulator) the whole cycle is performed in a closed system.The binder solution and powder mix are added at a fixed rate on the plate of the spheronizer so that the particles are stuck together and spheronized at the same time. Using this process Robinson and Hollenbeck18 prepared acetaminophen pellets and, in a comparison with extrusion–spheronization, they demonstrated that acceptable, immediate release pellets could be produced. A novel method involving the use of a rotary shaker pelletizer has been developed for making pharmaceutical spheres. It is essentially based on a laboratory shaker in which a cylindrical bowl is attached to the platform of a rotary shaker. Spiral particle motion combined with a high degree of particle bowl bottom friction and interparticulate collision in the bowl (feed with plastic extrudates) results in plastic deformation of extrudate and the granule surface to form the spheres19. A further technique used to prepare pellets is the layer building method, in which a solution or suspension of binder and a 161

reviews

research focus

drug is sprayed onto an inert core and the pellets are built layer after layer. However, use of this technique is limited because of the smaller drug loading that can be layered effectively onto the core material, thus making this technique unsuitable for drugs with large doses20. Extrusion and spheronization Extrusion and spheronization is currently one of the techniques used to produce pharmaceutical pellets. With each production technique, pellets with specific characteristics are obtained. The preparation of spherical granules or pellets by extrusion and spheronization is now a more established method because of its advantages over the other methods18,21 (Box 1), and the technique will now be described in detail.

Box 1. Advantages of the extrusion and spheronization process Ease of operation High throughput with low wastage Narrower particle size distribution Production of pellets with low friability Production of pellets that are suited for film coating More sustained and better controlled drug-release profile when compared with other techniques

Spheronization is a technique of Japanese origin that is sometimes referred to as Merumerization, after the trademark of the Fuji Denki Kogyo Company (Osaka, Japan). Although originally invented in 1964 by Nakahara22, it wasn’t until 1970 and the publication of the process by Reynolds (Lilly Research, UK)14 and Conine and Hadley (Eli Lilly, Indianapolis, IN, USA)23 that the technique became widely known. In subsequent years the detailed process of spheronization, including the individual processing variables based on extrusion and spheronization, was published by J.B. Schwartz’s group and the whole process was reduced to a series of pharmaceutical operations, each of which is associated with a number of individual parameters24,25. Process and equipment In basic terms, the extrusion and spheronization process involves four steps:

• • • •

granulation – preparation of the wet mass; extrusion – shaping the wet mass into cylinders; spheronization – breaking up the extrudate and rounding off the particles into spheres; drying – drying of the pellets.

162

PSTT Vol. 2, No. 4 April 1999

Different steps, parameters and equipment used in the process are summarized in Fig. 1. The first step of the extrusion and spheronization cycle consists of the preparation of the wet mass. Different types of granulators are used to perform the mixing of the powder blend and the granulation liquid. There are three types of processors used to mix different constituents of the powder blend. The most commonly used granulator is a planetary mixer18, although in various cases use of a high shear mixer, sigma blade mixer26 and a continuous granulator27 has also been reported. However, it is important to note that high shear mixers introduce a large amount of heat into the mass during granulation, which may cause evaporation of the granulation liquid because of a rise in temperature, thereby influencing the extrusion behaviour of the wet mass. This may be avoided by cooling the granulation bowl28. Extrusion Extrusion is the second step of the process and consists of shaping the wet mass into long rods, which are more commonly termed ‘extrudate’. The extrusion process is used not only in the pharmaceutical industry but also in the food, ceramic and polymer industries. The extrusion process is currently used as an alternative method for the manufacture of completely water-soluble tablets29. Types of extrusion devices have been grouped into four main classes; that is, screw, sieve and basket, roll and ram extruders. A screw extruder, as the name implies, utilizes a screw to develop the necessary pressure to force the material to flow through the uniform openings, producing uniform extrudates30. In the sieve and basket extruders the granulate is fed by a screw or by gravity into the extrusion chamber in which a rotating or oscillating device processes the plastic mass through the screen. The basket type extruder is similar to the sieve extruder except that the sieve or screen is part of a vertical, cylindrical wall31. The third class of extruders are the roll extruders and these are also known as ‘pellet mills’. Two types of roll extruders are available31,32. One extruder is equipped with two contrarotating wheels, of which one or both are perforated, and the second type of roll extruder has a perforated cylinder that rotates around one or more rollers that discharge the materials to the outside of the cylinder. The final type of extruder is an experimental device called the ram extruder.The ram extruder is believed to be the oldest type of extruder and features a piston riding inside a cylinder or channel that is used to compress material and force it through an orifice on the forward stroke. Fielden et al.32 compared the extrusion and spheronization behaviour of wet mass processed by a ram extruder and a cylinder extruder and concluded that they are not always equivalent.

research focus

PSTT Vol. 2, No. 4 April 1999

Granulating Powder dry liquid mixing

Coating solution

Mixer

Extruder

Spheronizer

Dryer

Coater

Wet mixing

Extrusion

Spheronization

Drying

Coating

Granulator type Granulation liquid Mixing time

Extruder type Extrusion speed Screen opening size Extrusion temperature

reviews

Figure 1. Flow diagram showing different steps, process parameters and equipment involved in extrusion and spheronization to produce spherical controlled release pellets.

Spheronizer Dryer type Drying temperature type Plate type Plate speed Spheronization time Spheronizer load

Spheronization The third step of the extrusion and spheronization process involves the dumping of the cylinders onto the spheronizer’s spinning plate, known as the friction plate, upon which the extrudate is broken up into smaller cylinders with a length equal to their diameter. A spheronizer is a device that consists of a vertical hollow cylinder (bowl) with a horizontal rotating disk (friction plate) located inside. The friction plate has a grooved surface to increase the frictional forces. Two types of geometry of the grooves exist; more common is the cross-hatch geometry in which the grooves intersect each other at 908 angles, whereas the other pattern is radial geometry in which grooves emanate from the centre like the spokes of a bicycle wheel.The spheronization of a product usually takes 2–10 minutes, and a rotational speed of between 200–400 rpm for the friction plate is satisfactory to obtain highly spherical pellets9,23. A special type of spheronizer, designed by NICA systems, features a lip around the rim of the friction plate that is claimed to reduce the milling effect of the plate in order to produce a smaller amount of fines30. The fourth and final step of the process is the drying of the pellets. The pellets can be dried at room temperature32 or at an elevated temperature in the fluidized-bed drier18, in an oven33, in a forced circulation oven13 or in a microwave oven34. Pellet quality is dependent on the type of dryer used. According to Bataille et al.34, oven drying provides less porous and harder minigranules and a more homogenous surface than those dried by a microwave oven. Dyer et al.35 prepared ibuprofen pellets that were dried either by tray drying or fluidized-bed drying, and they showed that the drying technique has a quantifiable effect on the diametral crushing strength and elasticity of the pellets, their in vitro release, and a qualitative effect on the surface characteristics of ibuprofen pellets. Pellet formation Numerous mechanisms of pellet formation have been suggested. The overall process of spheronization can be divided

into various stages in terms of the changes in the shape of the extrudate. According to Rowe36, extruded plastic cylinders are rounded in the form of pellets because of frictional forces. Cylinders transform into cylinders with rounded edges then to dumb-bells and elliptical particles and eventually to perfect spheres. Baert and Remon28 suggested that another pelletforming mechanism might also exist that is based on frictional forces as well as rotational forces. In this mechanism a twisting of the cylinder occurs after the formation of a cylinder with rounded edges, finally resulting in the breaking of the cylinder into two distinct parts with both parts featuring a round and a flat side. Because of the rotational and the frictional forces involved in the spheronization process, the edges of the flat side fold together like a flower, forming the cavity observed in certain pellets. Figure 2 shows both pellet-forming mechanisms. The process of extrusion and spheronizaton is a multi-step process that involves a number of parameters that have a final bearing on the characteristics of the obtained pellets. Moisture content is an extremely important parameter in the extrusion and spheronization process. It is necessary to give the powder mass its plasticity so that it can be extruded and shaped afterwards. It was (a)

I

II

III

IV

V

(b)

I

II

III

IV

V

Figure 2. Pellet-forming mechanism according to: (a) Rowe36 – I. Cylinder; II. Cylinder with rounded edges; III. Dumb-bell; IV. Ellipse; V. Sphere. (b) Baert – I. Cylinder; II. Rope; III. Dumb-bell; IV. Sphere with a cavity outside; V. Sphere. [Reproduced with permission from Ref. 9.]

163

reviews

research focus

shown that there is a certain limit of moisture content at which pellets of an acceptable quality are produced. If the moisture content is less than a certain lower limit, a lot of dust will be introduced during spheronization which will result in a large yield of fines. If moisture content is more than a certain upper limit then an overweighed mass and agglomeration of individual pellets during spheronization are caused because of an excess of water at the surface of pellet32. The extent of moisture content also influences the mechanical strength, friability, internal porosity and the particle-size distribution of pellets. Ostuka et al.37 reported that the internal porosity of spherical granules decreases with increasing water concentration, weight loss after the friability test increases with a decreasing amount of water and the quantity of water influences the mechanical strength of granules. Moisture content also affects the shape and size of granules38. Gazzaniga et al.39 found differences in the friability and particle size of pellets when the powder mass was wetted with different quantities of water. Starting material The physical nature of the starting material influences the particle size, hardness, and sphericity as well as the release rate of the included drug. There is not only the obvious difference in pellet quality produced from different compositions but also the difference when different types of the same product are used25.The use of similar products but from different suppliers has also been found to change the characteristics of the pellet40,41. Pellets prepared with three types of microcrystalline cellulose (MCC) – Avicel® PH-101, Emcocel®, Unimac® – MG from different manufacturers featured differences in size and roundness when processed under the same conditions40. The physical properties of two types of commercial MCC, Avicel PH-101 and Microcel MC show differences during the step of moistening, thereby affecting the particle size and hardness of the pellets obtained42.The difference in release rate in different types of dissolution medium has been observed between pellets containing only MCC and those containig MCC with sodium carboxymethyl cellulose (NaCMC). This difference is because a gel-like structure was formed in water through the presence of NaCMC with MCC, whereas the pellets containing only MCC remain unchanged in aqueous medium resulting in a greater rate of release43. Granulation liquid The use of different amounts of water as a granulation liquid alone or in combination with alcohol affects the hardness and particle size distribution of the final pellets. The most commonly used granulating liquid is water, although in some cases the use of alcohol or a water–alcohol mixture has also been reported9. The effect of the alcohol content in a water–alcohol 164

PSTT Vol. 2, No. 4 April 1999

mixture has been extensively studied by Millili and Schwartz44. Binary mixtures of theophylline and Avicel PH-101 (10:90 w/w) were found to form pellets when granulated with 90% ethylalcohol in water–alcohol mixture. Differences in friability and dissolution were observed between water granulated- and 95% ethylalcohol in water–alcohol mixture-granulated pellets. Increasing the water content in the granulation liquid leads to an increase in the hardness of the pellets. The increase in the hardness was correlated with a slower in vitro release rate of theophylline. Gazzaniga et al.39 reported that when bCyclodextrin (b-CD) was used to form pellets using water as the granulating liquid, the poor quality of the extrudates, in terms of plasticity and sticking, invariably lead to irregularly shaped pellets and agglomerates with broad size distribution. In this respect, preliminary promising results were obtained by lowering the solubility of b-CD in the wetting liquid through the use of water–alcohol mixtures. This probably improves the plasticity of the wetted mass and thus the feasibility of the overall process. Extruders Several studies appear in the literature regarding the influence of the type of extruder on the size distribution, sphericity and density of pellets14,36,41.The studies have shown that pellets obtained from two types of extruder had differed in sphericity and in particle size distribution because of a shift in the optimal amount of granulation liquid needed with each extruder or because of the difference in the length-to-radius ratio of the extrusion screen used45,46. According to Reynolds14 and Rowe36, an axial screw extruder produces a more dense material compared with the radial screw extruder; the latter has a higher output but also produces a greater rise in the temperature of the mass during processing. Extrusion screen properties Pellet quality is dependent on the extrusion screen, which is characterized by two parameters: the thickness of the screen and the diameter of the perforations. Changing one of these two parameters influences the quality of the extrudate and hence the pellets. Baert et al.46 reported the difference in extrudate quality when they were obtained by extrusion with different screen thicknesses. The screen with low thickness formed a rough and loosely bound extrudate, whereas the screen with high thickness formed smooth and well-bound extrudate because of the higher densification of the wet mass in the screen with the greatest thickness. Similarly, the diameter of the perforations determines the size of pellets, and a larger diameter in the perforations will produce pellets with a larger diameter when processed under the same conditions47,48. An increase in the extruder screen

research focus

PSTT Vol. 2, No. 4 April 1999

opening size was found to result in an increase in the hardness of the tablets made from these pellets25. Extrusion speed The total output of the extruder is mainly governed by the extrusion speed.The output should be as high as possible for economical reasons, but several authors state that an increase in the extrusion speed can influence the size and surface properties of the final pellets47–49. Several studies show that the surface impairments, such as roughness and sharkskinning, become more pronounced with increasing speed47,48.The surface effects of extrudate lead to pellets of lower quality because the extrudate will break up unevenly during the initial stages of the spheronization process, resulting in a number of fines and a wide particle-size distribution49. Extrusion temperature Extrusion temperature influences the pellet quality by affecting the moisture content. The rise in temperature during the extrusion cycle could dramatically alter the moisture content of granules because of evaporation of the granulation liquid. This may lead to a difference in the quality of the extrudate produced at the beginning of the batch and at the end of the batch. Evaporation of water during extrusion is possible because most of the water is available as free water50. Extrusion temperature control becomes an important parameter when a formulation with a thermolabile drug is processed. To avoid a rise in the temperature during an extrusion cycle, use of screw extruder with a cooling jacket around the barrel to keep the temperature of the given formulation between predetermined limit has been reported51,52. Spheronizer specifications Pellet quality is also dependent on spheronizer load. It mainly affects the particle size distribution, bulk and tap density of the final pellets9. The yield of pellets of a specific range decreases with an increase in the spheronizer speed and at a low spheronizer load, and increases with extended spheronization time at a higher spheronizer load53,54. Barrau et al.54 reported that an increasing spheronizer load decreased the roundness and increased the hardness of pellets, whereas yield in the majority size range remained unchanged. Hellen et al.55 reported that the bulk and tap density increased and the size of the pellets decreased with an increasing spheronizer load. The spheronization speed affects the particle size of pellets. In the initial stages of the spheronization process, an increase in the smaller fractions is seen, probably because of the greater degree of fragmentation. In contrast, a decreasing amount of fines and a higher amount of particles with faster spheronization speed correlating with an increased mean diameter was

reviews

also observed27,49,56. The hardness56, roundness49, bulk and tapped density55, porosity49,56, friability56, flow rate57 and surface structure56 of pellets are also affected by a change in the spheronization speed. Spheronization time mainly affects the particle size distribution53 and bulk and tap density55.57 of pellets. A wide range of results have been witnessed when assessing the importance of this parameter in formulations containing mixtures of MCC. These results include an observed increase in diameter, a narrower particle size distribution, a change in the bulk and tap density and a change in the yield of a certain size range with an extended spheronization time53. Development of oral CR formulations The advantages of using small spherical pellets or beads in oral controlled drug delivery are well documented. The pellets provide a smoother absorption profile from the GI tract, because the beads pass gradually from the stomach through the pyloric sphincter into the small intestine at a steady rate. Pellets can be layered with drug and coated with various polymers to control the release rates. Further, different types of pellets with different release rates can be combined in a simple capsule to provide the desired CR profile (Fig. 3). Betageri et al.58 have described three approaches to the preparation of sustained release pellets.

• • •

The first approach involves the placement of the drug in an insoluble matrix in which the eluting medium penetrates the matrix and the drug diffuses out of the matrix and into the surrounding pool for ultimate absorption. The second approach involves enclosing the drug particles with a polymer coat. In this case, the portion of the drug that has been dissolved in the polymer coat diffuses through an unstirred film of liquid into the surrounding fluid. The third approach is eroding beads in which the drug is released as the bead matrix erodes or dissolves.

In the first two cases the constant area of diffusion, together with a constant diffusion path length and constant drug concentration, can achieve a controlled rate of drug release. On the basis of the above approaches, the CR formulations prepared by extrusion and spheronization are mainly divided into two categories: coated pellets and matrix pellets. Coated pellets Controlled drug release from pellets is conventionally achieved by polymer coating. In many applications neutral pellets (nonpareil seeds) are used as raw materials that are coated with the active ingredients and then with release-retarding substances. According to the USP/NF monograph for sugar spheres59, neutral pellets consist mainly of sucrose and corn starch. The 165

reviews

research focus

PSTT Vol. 2, No. 4 April 1999

Drug blood level (amount mL−1)

Toxic range

Figure 3. Hypothetical drug blood level vs time profile, showing the relationship between controlled release and conventional release drug delivery. A 5 controlled release; B 5 prolonged release; C 5 conventional release.

Therapeutic range A

B Ineffective range

C

Time (h)

monograph specifies an upper limit of 4% for the water content and the variation in composition is 62.5–91.5% sucrose with the remainder consisting mainly of starch60. In the other case, the pellets containing active ingredients are prepared and then coated with a suitable rate-controlling polymer. In this case MCC is mainly used for the preparation of pellets containing active ingredients. Microcrystalline cellulose has the ideal physical properties, including moisture-retaining and distribution ability for extrusion and spheronization. This is most likely because of the favourable rheological properties of its wet mass61. In some cases, cellulose ethers, hydroxypropylmethyl cellulose (HPMC) and hydroxyethyl cellulose (HEC) are used as a pelletization aid62. Recently, the use of b-Cyclodextrin alone or in combination with different grades of MCC has also been reported39.The final prepared coated pellets can either be filled into two-piece hard gelatin capsules or compressed into tablets. Coating materials Film coating is effectively used to modify the release of active ingredients from pellets. Porter63 has defined the materials that are found to be suitable for the production of CR coatings.

• • •

Mixtures of waxes (such as beeswax and carnauba wax) with glyceryl monostearate, stearic acid, palmitic acid, glyceryl monopalmitate and cetyl alcohol. These provide a coating that dissolves slowly or breaks down within the GI tract. Shellac and zein – polymers that remain intact until the pH contents become less acidic. Ethylcellulose provides a membrane around the dosage form and remains intact throughout the GI tract. However, it does

166

• • •

permit water to penetrate the film, dissolve the drug and diffuse out again. Acrylic resins, which have similar properties to ethylcellulose as a diffusion-controlled drug release coating material. Cellulose acetate (triacetate and diacetate) – these provide a barrier coating and release depends on the pore structure of the membrane. Silicone elastomers – polymers are plastic-coating materials and drug liberation depends on the leaching of the drug from the inert matrix by GI fluid penetration into pores of plastic matrix.

Various studies have been reported in the literature on the use of coated pellets for CR. Controlled release beads of theophylline were developed by using ethyl cellulose as a coating material and were found to release theophylline in a controlled manner64. Similarly, Venkatesh and Sanghavi65 used extrusion and spheronization to prepare pindolol drug pellets that were coated with ethyl cellulose and eudragit RS100, and reported that drug release was influenced by the coating level and pH of the dissolution medium. Schultz and Kleinebudde66 prepared an acetaminophen system based on coated pellets containing an osmotic active ingredient, coated with a semi-permeable membrane of cellulose acetate, and the active ingredients were released according to zero-order kinetics. Aqueous polymeric dispersion coating Aqueous colloidal dispersions (latex and pseudolatex) of water-insoluble polymers are now increasingly used for coating solid dosage forms. The advantages of using such systems

research focus

PSTT Vol. 2, No. 4 April 1999

reviews

Table 1. Matrix system classification Hydrophilic

Inert

Lipidic

Biodegradable

Resin matrices

Unlimited swelling, delivery by diffusion Controlled delivery through limited swelling HPMC, HEC, HPC

Inert in nature

Delivery by diffusion

Nonlipidic in nature

Controlled delivery by diffusion Ethyl cellulose

Delivery by surface erosion Carnauba wax Bees wax Precirol

Controlled delivery by surface erosion Poly(anhydride), PLGA matrices

Drug release from drug–resin complex Release depends on the surrounding ionic environment Ion exchange resin

Abbreviations: HPMC, hydroxypropylmethyl cellulose; HEC, hydroxyethyl cellulose; HPC, hydroxypropyl cellulose; PLGA, copolymer (L-lactic/glycolic acid).

include efficient and predictable drug release, without possible agglomeration of the beads or pellets during the coating process. In addition, the use of toxic organic solvents in the process can be avoided.The mechanism of film formation from aqueous dispersions is a complex process. The aqueous polymer dispersion is sprayed onto the solid particles with suitable equipment and, as water evaporates, colloidal particles are forced to come together to form a film. Plasticizers are added to the film-forming polymer in order to improve the film-forming characteristics and to achieve a film with the desired permeability and drug release characteristics. Dyer et al.67 have prepared ibuprofen pellets by extrusion and spheronization and used an aqueous polymeric dispersion of polymethacrylates, ethylcellulose and silicon elastomer films in the coating. The application of a polymeric membrane to uncoated cores had the effect of retarding drug release. Matrix pellets, systems and classification Sustained release from pellets is conventionally achieved by polymeric coating. There is growing interest in the development of matrix pellet formulations because, in practice, polymeric coating is associated with various problems68.

• • • • •

The process is time consuming and expensive. Film thickness is variable. There may be cracks in the film or aging of the polymer coating. The drug release profile is not reproducibile because of inconsistent film coating. Coating is dependent on the optimization of several parameters during the production process.

Amongst the innumerable methods used for controlling the drug release from a pharmaceutical dosage form, the matrix system is the most frequently applied method. The matrix system is a heterogeneous dispersion of drug particles in a solid matrix, which can either be biodegradable or nonbiodegrad-

able and controls the drug release by diffusion through the matrix, by erosion of the matrix, or by a combination of both diffusion and erosion69–71. To define a matrix, the following properties must be considered:

• • • • •

chemical nature of support (generally the supports are formed by polymeric nets); the physical state of the drug (dispersion under molecular or particulate form, or both); the matrix and alteration in volume as a function of time; the routes of administration (oral administration remains the most widely used but other routes are adaptable); the release kinetics model (in accordance with Higuchi’s equation, these systems are considered to have a linear release as a function of the square root of time).

The matrix-based systems can be classified on the basis of the following criteria70:

• • • •

matrix structure; release kinetics (must be zero-order release); CR properties (diffusion, erosion and swelling); chemical nature and properties of the applied materials.

With regard to the last criterion, the matrix system can be classified into five main classes (Table 1). Several studies have shown that it is possible to formulate matrix pellets using extrusion and spheronization. Different Avicel products25, blends of Avicel products72, a series of release-retarding agents73, and Avicel with waxes74 have been incorporated into bead formulations to retard drug release. A product with Avicel and sodium carboxymethyl cellulose content showed a slower rate of release in water25,72; this has been attributed to the formation of a gel plug in the USP dissolution basket.The formation of a gel plug is probably due to coalescence of beads in the basket, but importantly, the purpose of multi-unit dosage forms is lost. 167

reviews

research focus

PSTT Vol. 2, No. 4 April 1999

Bioavailability studies of a hydrochlorothiazide pellet formulation consisting of Avicel RC-581 (containing 11% NaCMC) did not suggest a slow rate of release in vivo43. The release of indobufen can be modified by using combinations of pH adjusters (citric acid, sodium citrate, tartaric acid and fumaric acid) and polymeric dispersions and by employing Avicel PH-101 as a spheronizing aid.The presence of pH adjusters in pellet formulations affects the microenvironment of the drug molecule, producing different CR profile patterns, although the extent of slow release was limited49 (80% released in 4 h). Polymeric dispersions Aquacoat ECD 30 and Eudragit RS 30 D were used in combination with Avicel PH-101 or Avicel RC-591 to produce acetaminophen and ibuprofen beads. Ibuprofen release was retarded significantly when formulated at low drug loading (10%) with higher amounts of polymeric dispersion. Avicel RC-591 was an effective aid in successful spheronization at a higher drug loading and when greater amounts of polymeric dispersions were used (as presented by Goskonda, S.R., Upadrashta, S.M. and Hileman, G.A. at the American Association of Pharmaceutical Scientists’ Midwest Regional Meeting, 1992, Chicago, IL, USA). In another study using a zwitterion (isoelectric point ~pH 5.2) as a model drug, it was found that the combination of Eudragit RS-30 D with an organic acid as a pH modifier (fumaric acid and succinic acid) and Avicel RC-591 in the bead could yield a product that exhibits sustained release75,76. Release rate modification Various release-retarding materials have been incorporated to modify the release rate. Chitosan and Avicel RC-591 were used as matrix materials for retarding drug release33,77. Peh and Yuen78 prepared matrix pellets using glyceryl monostearate with a satisfactory in vitro dissolution rate. The authors reported

that the rate of drug release could be modified in a predictable manner by varying the amount of glycerylmonostearate in the formulation. Blanque et al.79 utilized a combination of glycerylmonostearate and barium sulphate, the water-insoluble filler, to retard the drug-release rate. Neau et al.80 reported the feasibility of employing Carbopol® 974, NF resin as a sustainedrelease modifying agent. In these studies, the authors utilized the chemical interaction between electrolytes and Carbopol® 974P to reduce the tackiness of the latter in pellet formulations. They also successfully prepared Chlorpheniramine maleate/MCC pellets with up to 55% w/w Carbopol® 974P by incorporating strong electrolytes such as sodium chloride, calcium chloride, magnesium chloride and aluminium chloride. A recent study indicated that diltiazem hydrochloride release could be modified by using magnesium stearate as a hydrophobic release modifier81. The feasibility of using plastic materials, such as HPMC, as a binder and release modifier was also tested, and the authors reported that because of the plastic nature of HPMC, formulations were difficult to spheronize. However, the cylindrical extrudate, obtained as the final product, showed a CR profile. The incorporation of waxes into a MCC matrix resulted in faster release from beads because of matrix interruption, whereas thermal treatment of the same beads resulted in sustained drug release64. Of several waxes, only a few waxes, such as spermaceti, precirol, beeswax and castor wax, proved to be sufficiently effective in retarding drug release. However, little research into this approach has been performed because of a lack of excipients and polymers with the required physical characteristics, thus making them unsuitable to be used for extrusion and spheronization. At present, various CR formulations that utilize pellets are available, and some are summarized in Table 2.

Table 2. Different controlled-release marketed products in the form of pellets Formulations

Active components

Manufacturers

Betacap TR capsules Coldact TR capsules

Propanolol hydrochloride Phenylpropanolamine hydrochloride and chlorpheniramine maleate Diltiazem hydrochloride Zn + iron + folic acid Ibuprofen Indomethacin Pseudoephedrine hydrochloride Anhydrous theophylline Theophylline Salbutamol

Natco Pharma Natco Pharma

Dilgard XL ER capsules FEFOL®-Z SR capsules Ibubid TR capsules Indocap® capsules Sudafed SA capsules Theo-24 SR capsules Theolong SR lungules Ventorlin CR capsules

Abbreviations: CR, controlled release; SA, sustained action; SR, sustained release; TR, timed release.

168

Cipla SmithKline Beecham Pharmaceuticals Natco Pharma Jagsonpal Pharma Borroughs–Wellcome Searle Pharmaceuticals SOL Pharma Glaxo India

research focus

PSTT Vol. 2, No. 4 April 1999

Conclusions Extrusion and spheronization is an effective technique for the preparation of CR multiparticulate formulations of bioactive agents. There are currently various multiparticulate CR formulations available, and the success of this process is largely dependent on its advantages over other techniques. The spherical granules or pellets produced by this technique feature a regular shape with uniformity in size and density. When dry, the spheroids have an extremely low friability and are ideally suited for film coating. In addition, the process is capable of high throughput with low wastage and easy operation. With the increasing use of multiparticulate CR formulations, it is envisaged that extrusion and spheronization will become a popular and well known process in the near future.

26

Ku, C.C. et al. (1993) Drug Dev. Ind. Pharm. 19, 1505–1519

27

Hellen, L. and Yliruusi, J. (1993) Int. J. Pharm. 96, 217–223

28

Baert, L. and Remon, J.P. (1993) Int. J. Pharm. 95, 135–141

29

Murphy, M.P. and Hollenbeck, R.G. (1998) Pharm.Technol. 22(4), 94–102

30

Hellen, L. et al. (1992) Pharm.Tech. Int. Biophys 4, 50–60

31

Hicks, D.C. and Freese, H.L. (1989) in Pharmaceutical Pelletization Technology (Ghebre-Sellassie, I., ed.), pp. 71–100, Marcel Dekker

32

01 02

33

Goskonda, S.R. and Upadrashta, S.M. (1993) Drug Dev. Ind. Pharm. 19, 915–927

34 35

Bataille, B. et al. (1993) Drug Dev. Ind. Pharm. 19, 653–671 Dyer, A.M., Khan, K.A. and Aulton, M.E. (1994) Drug Dev. Ind. Pharm. 20, 3045–3068

37

Berner, B. and Dinh, S. (1992) in Treatise on Controlled Drug Delivery

Rowe, R.C. (1985) Pharm. Int. 6, 119–123 Ostuka, A.M., Gao, J. and Matsuda,Y. (1994) Drug Dev. Ind. Pharm. 20, 2977–2992

(Kydonieus, A., ed.), pp. 1–29, Marcel Dekker

38

Fielden, K.E., Newton, J.M. and Rowe, R.C. (1993) Int. J. Pharm. 97, 79–92

Lordi, N.G. (1986) in The Theory and Practice of Industrial Pharmacy (Lachman, H.A.

39

Gazzaniga, A. et al. (1998) Drug Dev. Ind. Pharm. 24, 869–873

and Kang, J.L., eds), pp 430–456, Lea and Febiger, Philadelphia, PA, USA

40

03

Hussay, U.K. et al. (1991) J. Clin. Pharmacol. 31, 361–364

04

Katznendler, I. et al. (1997) J. Pharm. Sci. 86, 110–115

05

Nellore, R.V. et al. (1998) J. Control. Release 50, 247–256

06

Gupta, P. et al. (1996) Eur. J. Pharm. Biopharm. 42, 74–81

42

07

Vandelli, M.A., Leo, E. and Forni, F. (1995) Eur. J. Pharm. Biopharm. 41,

43

Newton, J.M., Chow, A.K. and Jeewa, K.B. (1992) Pharm.Tech. Int. Biophys. 4, 52–58

41

Law, M.F.L., Deasy, D.B. and Mclaughlin, J.P. (1997) J. Microencapsulation 14, 713–723

262–265 08

Fielden, K.E., Newton, J.M. and Rowe, R.C. (1992) Int. J. Pharm. 81, 222–233

36

References

reviews

Sonagllo, D. et al. (1995) Drug Dev. Ind. Pharm. 21(5), 533–547 Herman, J., Remon, J.P. and Lefebure, R. (1988) J. Pharm. Pharmacol. 40, 157–160

Parikh, B.M. (1990) Alternatives for Processing Spherical Granules, paper presented

44

Millili, G.P and Schwartz, J.B. (1990) Drug Dev. Ind. Pharm. 16, 1411–1426

at Interphex USA, 10 May, New York, NY, USA

45

Baert, L. et al. (1992) Int. J. Pharm. 86, 187–192

09

Vervaet, C., Baert, L. and Remon, J.P. (1995) Int. J. Pharm. 116, 131–146

46

Baert, L. et al. (1993) Int. J. Pharm. 99, 7–12

10

Eskilson, C. (1985) Manuf. Chem. 56(3), 33–39

47

Hellen, L. et al.(1993) Pharm.Tech. Int. Biophys. 5, 44–53

Bechgaard, H. and Hegermann-Nielsen, G. (1978) Drug Dev. Ind. Pharm. 4,

48

11

53–67 12

Harrison, P.J., Newton, J.M. and Rowe, R.C. (1985) J. Pharm. Pharmacol. 37, 81–83

Ghebre-Sellassie, I. (1989) in Pharmaceutical Pelletization Technology (Ghebre-

49

Bianchini, R. et al. (1992) Drug Dev. Ind. Pharm. 18, 1485–1503

Sellassie, I., ed.), pp. 1–13, Marcel Dekker

50

Fielden, K.E. et al. (1988) J. Pharm. Pharmacol. 40, 674–678

13

Govender,T. and Dangor, C.M. (1997) J. Microencapsulation 14, 445–455

51

Dietrich, R. and Brausse, R. (1988) Pharm. Ind. 50, 1179–1186

14

Reynolds, A.D. (1970) Manuf. Chem.Aerosol News 41, 40–43

52

Kleinebudde, P. and Linder, H. (1993) Int. J. Pharm. 94, 49–58

15

Bechard, S.R. and Leroux, J.C. (1992) Drug Dev. Ind. Pharm. 18, 1927–1944

53

16

Canefe, K. and Comoglu,T. (1997) J. Control. Release 48, 343

17

Mathir, J.M. et al. (1997) J. Microencapulation 14, 743–751

54

Barrau, J.P., Bataille, B. and Jacob, M. (1993) Pharm.Technol. Int. 66, 68–70

18

Robinson, R.L. and Hollenbeck, R.G. (1991) Pharm.Technol. 15(7), 48–56

55

Hellen, L. et al. (1993) Int. J. Pharm. 96, 197–204

19

Jaiswal, S.B. et al. (1995) Drug Dev. Ind. Pharm. 21, 2109–2120

56

Bataille, B. et al. (1993) Drug Dev. Ind. Pharm. 19(6), 653–671

20

Chambliss, W.G. (1989) in Pharmaceutical Pelletization Technology (Ghebre-

57

Malinowski, H.J. and Smith, W.E. (1975) J. Pharm. Sci. 64, 1688–1692

Sellassie, I., ed.), pp. 15–38, Marcel Dekker

58

21

Zhang, G. et al. (1991) Drug Dev. Ind. Pharm. 17, 817–830

22

Nakahara, N. (1964) US Patent 3 227 520

23

Conine, J.W. and Hadley, H.R. (1970) Drug Cosmet. Ind. 106, 38–41

24 25

Newton, J.M., Chapman, S.R. and Rowe, R.C. (1995) Int. J. Pharm. 120, 101–109

Betageri, G.V., Kurumaddali, K.R. and Ravis, W.R. (1995) Drug Dev. Ind. Pharm. 21, 265–275

59

The United States Pharmacopoeia/National Formulary (1995) (Asian edition), p. 2313,The United States Pharmacopoeial Convention, Inc.,

O’Connor, R.E., Holinej, J. and Schwartz, J.B. (1984) Am. J. Pharm. 156,

Rockville, MD, USA

80–87

60

Werner, D. (1996) Pharm. Manuf. Rev. 8, 26–29

O’Connor, R.E. and Schwartz, J.B. (1985) Drug Dev. Ind. Pharm. 11,

61

Shah, R.D. et al. (1995) Pharm. Res. 12, 496–507

1837–1857

62

Chatlapalli, R. and Rohera, B.D. (1998) Int. J. Pharm. 161, 179–193

169

reviews

63

research focus

PSTT Vol. 2, No. 4 April 1999

Porter, S.C. (1995) in Remington – The Science and Practice of Pharmacy,

72

pp. 1651–1660, Mack Publishing Company, PA, USA 64

Yuen, K.H., Deshmukh, A.A. and Newton, J.M. (1993) Drug Dev. Ind. Pharm.

73

19, 855–875

74

65

Venkatesh, H. and Sanghavi, N.M. (1994) Drug Dev. Ind. Pharm. 20, 111–118

66

Schultz, S.P. and Kleinebudde, P. (1997) J. Control. Release 47, 181–184

67

Ghali, E.S., Klinger, G.H. and Schwartz, J.B. (1989) Drug Dev. Ind. Pharm. 15, 1455–1473 Ghali, E.S., Klinger, G.H. and Schwartz, J.B. (1989) Drug Dev. Ind. Pharm. 15, 1311–1328

75

Dyer, A.M., Khan, K.A. and Aulton, M.E. (1995) Drug Dev. Ind. Pharm. 21, 1841–1858

Briquet, F. et al. (1986) STP Pharma. 2, 986–994

Goskonda, S.R., Hileman, G.A. and Upadrashta, S.M. (1994) Int. J. Pharm. 111, 89–97

76

Goskonda, S.R., Hileman, G.A. and Upadrashta, S.M. (1994) Drug Dev. Ind.

68

Zhou, F.,Vervaet, C. and Remon, J.P. (1996) Int. J. Pharm. 133, 155–160

Pharm. 20, 279–292

69

Veiga, F., Salsa,T. and Pina, M.E. (1998) Drug Dev. Ind. Pharm. 24, 1–9

77

Tapia, C., Buckton, G. and Newton, J.M. (1993) Int. J. Pharm. 92, 211–218

70

Salsa,T.,Veiga, F. and Pina, M.E. (1997) Drug Dev. Ind. Pharm. 23, 929–938

78

Peh, K.K. and Yuen, K.H. (1995) Drug Dev. Ind. Pharm. 21, 1545–1555

71

Hui, H.W. and Robinsons, J.R. (1987) in Controlled Drug Delivery Fundamentals

79

Blanque, D. et al. (1995) Int. J. Pharm. 119, 203–211

and Applications (Robinson, J.R. and Lee,V.H.L., eds), pp. 374–420, Marcel

80

Neau, S.H., Chow, M.Y. and Durrani, M.J. (1996) Int. J. Pharm. 131, 47–55

Dekker

81

Sood, A. and Panchagnula, R. (1998) J. Pharm. Pharmacol. 50, 181

In brief… Imperial College Innovations (London, UK) has agreed a licensing option with Millennium BioTherapeutics (Cambridge, MA, USA) for the use of patent-protected leptin antagonist technology. Robert Lechler has developed the technology within Imperial College Innovations, the technology development company for the Imperial College of Science, Technology and Medicine, and his group is evaluating the effects of leptin and its antagonists on immune system activity. Leptin, primarily associated with obesity, has been found to increase in primary immune response and to reverse the reduction in the hypertensive response induced by starvation, a result with implications of immunization, particularly in areas of malnutrition. Leptin antagonists may have an immunosuppressive effect, with potential for exploitation in transplantation or treatment of autoimmune disorders. Millennium BioTherapeutics is a majority owned subsidiary of Millennium Pharmaceuticals and has acquired the option for the field of human immunosuppressive therapy, and is also providing reagents for Lechler’s group. Jonathan Gee, Chief Executive of Imperial College Innovations commented, ‘This is another example of the excellent research carried out within Imperial College having real commercial potential, an issue of increasing importance in universities. I anticipate that this work could prove extremely valuable in the development of novel therapies in different areas including cancer and immunosuppression.’

In the May issue of Pharmaceutical Science & Technology Today… Update – latest news and views Potential for plasmid DNAs vaccines for the new millennium Khushroo E. Shroff, Larry R. Smith, Yaela Baine and Terry J. Higgins Targeting endocytosis and motor proteins to enhance DNA persistence Sarah F. Hamm-Alvarez Coated dosage forms for colon-specific drug delivery Claudia S. Leopold Imaging techniques for assessing drug delivery in man Stephen P. Newman and Ian R. Wilding Monitor – process technology, drug delivery, analytical methodologies, legislative issues, patents, invited profile

170