Fridrun Podczeck is professor of pharmaceutics at Sunderland School of Pharmacy, University of Sunderland, UK

Fridrun Podczeck

  the preparation of pellets by extrusion/spheronization has become a well-documented and accepted commercial process. Most pellet formulations on the market and most studies of this process are based on the use of microcrystalline cellulose (MCC) as a spheronization agent to ensure the process functions well. However, MCC cannot provide a formulation for all drugs. For many drugs it is also not possible to incorporate high-drug doses into MCC pellets. Even when pellets can be prepared, there could be problems regarding chemical instability of the drug, as reported, for example, for ranitidine.

A disadvantage of using MCC is the high costs of the material, especially as large quantities of at least 50% w/w or more are required in a formulation, which also restrict the maximum dose of drug that can be incorporated to ensure a reasonably small size of a capsule or a tablet. A number of reports have demonstrated considerable product variability because of the source ('brand') and grade variability of MCC,

  with respect to the extrusion/spheronization process, and some cheaper brands have been suspected not to function very well.

For the formulations to extrude and change shape during the spheronization process, it is necessary to add larger amounts of liquid binder to achieve a plastic wet mass. The liquid binder is preferably water or a mixture of water with ethanol, glycerol or self-emulsifying systems. The use of organic solvents is very restricted under industrial manufacturing conditions. Pellets based on MCC as a spheronization aid do not disintegrate and they release the drug rather slowly and often incompletely. However, the drug release is not slow enough to produce an extended release dosage form and the application of modified release film coatings is required. There are also reports on the influence of various processing parameters, such as standing time of the wet mass on the quality of the final pellets,

  which are of concern to the industry where material and product intermediate hold-ups cannot always be avoided. 

One approach to provide alternative excipients to aid the process of extrusion/spheronization has been the modification of the standard grades of MCC by co-processing the wet cake with hydrophilic polymers such as polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC) or sodium carboxymethylcellulose;

  the latter having been shown to perform better in terms of increasing the drug level that can be incorporated into the pellets.

In recent years, there has also been a series of publications showing the ability of a range of excipients to act in a similar capacity to MCC. Examples include carrageenan,

  However, none of these materials have as yet been subjected to the same degree of evaluation as MCC, and some have limitations; for example, HPMC and HEC require the use of isopropyl alcohol as the binder liquid,

  which may be useful for water-sensitive drugs, but is restrictive in practical manufacturing terms.  

When studying glyceryl monostearate, only one of the four model drugs tested provided good quality pellets.

  Chitosan required the binder liquid to be 0.2 M acetic acid.

  The use of starch required more effort than simple addition of water by mixing,

  which is the method used for MCC. From the data provided in many of the above publications, it is difficult to judge the quality of the pellets in terms of their roundness and narrowness of particle size distribution, both being an essential requirement for the product to be manufactured under industrial conditions. Inspection of photographs provided in these publications would suggest that the pellets were rather 'rounded' (i.e., still being considerably elongated with rounded edges, rather than spherical). This would indicate that the alternative spheronizing aids studied lacked plasticity and would not be a universal replacement for MCC in the pharmaceutical industry. 

The criteria that ensure an excipient will function as an aid to extrusion/spheronization are not known with certainty. Excipients need to have a binder liquid — usually water — holding capacity, especially when the wet mass is subjected to pressure.

 indicated that water retention capacity alone may not be the only factor involved in the performance of spheronization aids.

  The rheological properties of the system are also important, but as systems with a wide range of rheological properties will make satisfactory pellets,

  this remains to be clearly defined. From measurements of the rheological properties of the wet mass of MCC containing a large quantity of lactose monohydrate, MacRitchie 

 suggested that the elastic properties of the wet mass should also be at an optimum level.

A pharmaceutically acceptable excipient, which has a high retention capacity for water, is colloidal silicon dioxide.

  Preliminary experiments with this material proved unsuccessful under a wide range of conditions. However, with the addition of a non-ionic surfactant to the aqueous liquid binder, it is possible to form good quality pellets using this material as an aid to extrusion/spheronization.

Colloidal silicon dioxide (CSD) Ph. Eur. was obtained as Aerosil 200 (Degussa Ltd, UK). The fillers were lactose monohydrate Ph. Eur. (Borculo Whey Products, UK) and heavy magnesium carbonate Ph. Eur. (Thornton & Ross, UK). The model drug used was ephedrine hydrochloride Ph.Eur. (S&D Chemicals Ltd, UK). Purified polyoxy–35–castor oil Ph.Eur. (Cremophor ELP; BASF, Germany) was used as model non-ionic surfactant, Imwitor 742 (Condea Chemie GmbH, Germany) was used as a plasticizer and freshly distilled water was used as a liquid. 

 The appropriate quantities of powder and plasticizer, as set out in Table 1, were first dry mixed in a planetary mixer (Model A901E; Kenwood Chef, UK) for 5 min. A 5% w/w solution of Cremophor ELP in water was gradually incorporated into the mixture, which was mixed for a further 10 min, with scraping the sides and bottom of the bowl and mixing blades performed at 5 min intervals during the process. The amount of binder liquid solution required to produce round pellets with a narrow size distribution was obtained by trial and error. The wet mass was extruded with a radial extruder (Model 10 Extruder; G.B. Caleva Ltd, UK) and fitted with a screen of 1.5 mm thickness with 1.5 mm diameter holes. Quantities of 30 g of extrudate were spheronized for 10 min on a 125 mm cross-hatch plate in a spheronizer (Model 120; G.B. Caleva Ltd, UK). The speed of rotation was optimized in a systematic fashion for each formulation (Table 1). Considering the small batch size, the pellets were dried at room temperature (22–24 °C) and 50–55% RH by storing them on sieves with 0.355 mm mesh size, until a constant weight was obtained. 

 Table 1 Composition including optimized liquid binder concentration and optimum spheronization speed for pellets made with CSD.			

 The size distribution of the pellets was determined using a mechanical sieve shaker (Type 47–300; Retsch, UK) fitted with a root–2 progression of British Standard Sieves (Endecotts, UK) between 500 and 4000 μm. The amount of pellets in the size fractions below 710 μm and above 2 mm were found negligible in most cases. 

, first described by Podczeck and Newton,

  were determined by image analysis. The measurements were conducted with a Seescan image analyser (Seescan Solitaire 512; Seescan Imaging, UK) attached to a black and white camera (CCD-4 miniature video camera, Rengo Co. Ltd, Japan) and fitted to a zoom lens (18-108/2.5; Olympus Europe, Germany). The resolution was set to 18 μm/pixel and was calibrated with a graticule (Macro systems, UK). One hundred pellets from the 1.0–1.4 mm sieve fraction of each batch were randomly selected. The pellets were mounted on a surface painted with nonreflective black paint and illuminated from above with a twin cold light source adjusted at 180° to the surface (Olympus Highlight 3001; Olympus Europe, Germany) to minimize the formation of shadows. These conditions were followed to satisfy the requirements set out by Podczeck 

 The load required to break 50 randomly selected pellets from the 1.0–1.4 mm size sieve fraction of each batch was determined using a physical testing instrument (CT-5; Engineering Systems, UK) fitted with a 5 kg load cell and using a cross-head speed of 1 mm/min. From the breaking load, the value of the surface tensile strength of the pellets could be calculated as described by Salako 

The pellet density was measured with a helium pycnometer (MVP-1; Quanta Chrome Corp., NY, USA) as outlined in Ph.Eur. (Appendix XVII K, method 2.9.23). Five replicated measurements were done per batch. From a measurement of the helium particle density of the constituent powders and their proportion in the final pellets, the porosity of the pellets could be determined. 

Disintegration and drug release from the pellets. 

The drug release from the pellets was assessed according to the Ph.Eur. dissolution apparatus II procedure, with a paddle speed of 50 rpm in 900 mL of distilled water at 37±0.5 °C for 30 min. The pellets were monitored and the time taken for them to disintegrate during the dissolution test was recorded. This was preferred over a standard disintegration test, which is more vigorous in agitation and may not reflect the conditions encountered during the dissolution test. 

Six samples of 300 or 600 mg of pellets, depending on the drug content, were tested. The amount of drug released into the solution at 5 min time intervals was assessed spectrophotometrically at a wavelength of 271 nm with a UV spectrophotometer (Model CE272; Cecil Instruments, UK). 

Pellet preparation by extrusion/spheronization.

 Pellets could be produced from all formulations tested. One important feature of these formulations is that pellets can be prepared from CSD without the addition of any bulking agent or drug (Table 1, Formulations 11 and 12). This is also possible with MCC, but for CSD the binder liquid must contain the non-ionic surfactant and the optional addition of the plasticizer Imwitor 742 is possible. The amount of liquid binder solution added is more than twice the weight of the CSD powder and only slightly reduced by the addition of the plasticizer. CSD can take up water up to 40% of its own weight without losing its appearance as free-flowing powder. It is, therefore, not surprising that such a large amount of liquid binder is needed to transform the material into a wet mass with sufficient plasticity to enable extrusion. In the formulations containing ⅓ of CSD and ⅔ of drug and/or filler, the ratio between the CSD and the amount of liquid binder added remains at approximately 1:2 when soluble formulation components have been added and increases to 1:3 for the formulations containing only the insoluble filler magnesium carbonate. Whether or not the plasticizer has been added to the formulations seems to have no effect. 

Another feature of the CSD formulations appears to be their sensitivity to the speed of rotation during the spheronization step (Table 1). CSD extrudates can be spheronized at a higher speed of rotation than formulations containing drug and/or filler in addition to CSD. However, the related linear peripheral velocity value of 9.7 m/s is considerably smaller than that commonly used for MCC containing formulations (23.6 m/s). Because of the relatively larger amount of liquid incorporated into the plain CSD formulations, the extrudate is heavier and less prone to elastic bouncing on the spheronization plate. For magnesium carbonate mixtures, the relative amount of liquid binder added is reduced to approximately half, but the high density of this excipient adds weight, preventing elastic bouncing of the extrudate. However, when the less dense drug and/or lactose monohydrate is added to CSD, the extrudates are very elastic and the speed of the spheronizer plate must be further reduced and tightly controlled. Sensitivity of formulations to the spheronization speed has been previously reported by Speirs

  for formulations containing large amounts of the disintegrant croscarmellose sodium. As can be seen from Table 1, the addition of a plasticizer in small quantities does not influence the optimum spheronization speed. 

 When evaluating the results for the sieve analysis reported in Table 2, it should be borne in mind that a screen with a diameter and length of the die bores of 1.5 mm was used for the extrusion. This choice had been made to increase the length of the dies and, therefore, the pressure and densification of the extrudate. Initially, a smaller screen of 1 mm die length and thickness had been used, resulting in shark-skinned and very brittle extrudate that broke during the spheronization process. The change in the screen was successful in preventing shark skinning and indicates that the CSD formulations will perform even better when extruded with long die extruders. A wet mass extruded through 1.5 mm die bores should be expected to result in pellets of approximately 1.5 mm diameter or even more. Hence, considerably smaller pellet sizes are an indication of brittleness of the extrudate. This can be seen for pellets made from CSD only, as the modal fraction for these two formulations is the sieve fraction 0.71–1.0 mm. Pellets made from CSD and the drug are of a modal size range of 1.4–2.0 mm, and their extrudate is least brittle. Pellets made from CSD and either lactose monohydrate or magnesium carbonate are smaller (modal size fraction 1.0–1.4 mm), but the addition of drug to these formulations, again, results in an increase in the modal pellet size. 

The pellet shape has been assessed using two parameters. The aspect ratio is sufficient for industrial inprocess control of pellet formulations during manufacture and an upper limit of 1.2 has been stated for the use of pellets in, for example, capsule filling.

  The results presented in Table 2 indicate that ⅔ of the formulations produced would fill into capsules without any problems. The pellets made from CSD only, and those made from a mixture of equal parts of drug, lactose monohydrate and CSD in the powder mixtures, however, are just outside the recommended limit. The addition of the plasticizer did not improve the shape formation of these formulations, but a change of the filler from lactose monohydrate to magnesium carbonate resolves this issue (i.e., when formulating pellets using CSD as the spheronization aid, the selection of an appropriate filler can improve the product properties considerably).  

Second, as conducted in research, the shape of the pellets was more scrutinized using the shape factor 

, which is largely reflecting the overall macro-surface properties of pellets as well as their elongation. A pellet might appear fairly round visually, but surface irregularities (e.g., bumps, flattening, etc.) will considerably reduce the value for this shape factor. A 'perfect' sphere with smooth surfaces would present a value of approximately 0.6.

  As can be seen from Table 2, none of the pellet batches has perfectly round and smooth pellets. However, as Figure 1 shows, most pellets are well rounded, yet their surface is rougher than that of MCC pellets. Figure 2 shows a larger set of pellets for batch ALEc_i, which was the least round batch of pellets, but which had a very narrow particle size distribution with more than 72% of all pellets in the modal fraction. The values of the shape factor 

 seem, in some instances, related to the pellet porosity (i.e., the less porous the pellets, the better is their shape). This indicates that the use of long die extruders might further improve the pellet properties in terms of their shape. 

 Pellets made only from CSD were very fragile and had insufficient strength for an accurate measurement. After addition of the drug and/or excipient to the formulation, the pellet strength was much improved (Table 2). However, the addition of the plasticizer resulted in a decrease in pellet strength and in two instances the pellets did not fracture but deformed plastically during the tests. Therefore, in terms of pellet strength the addition of the plasticizer is not recommended. Pellets without plasticizer, but containing the drug, have sufficient strength to undergo further processing such as film coating or capsule filling. 

Pellets disintegrated rapidly on contact with the dissolution liquid and after 10 min had disintegrated into their powder components. This is in contrast to MCC pellets, which disintegrate incompletely or not at all.

  Figure 3 shows the dissolution profiles for the six formulations containing the drug. Because the pellets disintegrated, the figure reflects the dissolution properties of the drug particles of the disintegrated pellets rather than the influence of the pellet formulations. Addition of the plasticizer increased the dissolution rate of the drug slightly in all cases. Also, pellets containing the insoluble filler, magnesium carbonate, had the slowest disintegration time and show slightly slower drug release rates. 

It can be concluded that CSD can be used as a spheronization aid, provided that 5% of a non-ionic surfactant, such as Cremophor ELP, is added to the binder liquid water. The pellets would have better properties if the extrusion process results in a larger degree of densification, which could, for example, be achieved using a long die extruder. The extrudate is elastic and speed sensitive, and slow and well-maintained spheronization speeds are required. The addition of a plasticizer does not improve the performance of the formulations and is, hence, not essential. In contrast to MCC pellets, pellets made with CSD as a spheronization aid disintegrate rapidly when in contact with dissolution liquid and therefore ensure a better and more complete drug release from the pellets. 

The author would like to acknowledge the assistance of Nuno Miguel Da Silva Carvalho with the practical work.  

 is Visiting Professor at the Department of Mechanical Engineering at University College London (UK). 

2. A. W. Basit, J.M. Newton and L.F. Lacey, 

4. C.L. Raines, "Rheological Properties of Different Grades of Microcrystalline Cellulose," Ph.D. Thesis, University of London, UK (1990). 

Rheology of Food, Pharmaceuticals and Biological Materials with General Rheology

 (Elsevier Applied Science, London, UK 1990) pp 248–257. 

10. I. Jover. F. Podczeck and J.M. Newton, 

Articles

Microcrystalline cellulose is the main excipient used in the industrial manufacture of pellets by extrusion/spheronization, but pellets containing this spheronizing aid do not readily disintegrate and are expensive.

A novel aid for the preparation of pellets by extrusion/spheronization

Last year, the Royal Pharmaceutical Society of Great Britain held a consultation regarding how the profession should develop during the next 12 years. An analysis of the results has just been published.

  It comes as no surprise to anyone who teaches pharmaceutics at UK pharmacy departments that one popular suggestion was to change the indicative syllabus so that it would focus more on clinical topics as opposed to scientific ones. 

Undergraduate pharmacy students find it difficult to cope with science-based teaching, and the average marks in pharmaceutics exams are usually lower than those in clinical or pharmacy practice topics. Pharmaceutics — in particular formulation, physical pharmacy and pharmaceutical technology — requires good knowledge of mathematics and physics, but the UK entry requirements for pharmacy do not include A Level qualifications in these disciplines. The degree courses do not have room for these topics to be introduced, nor would most students be interested in such fundamental studies. Additionally, the situation is made worse by the lack of funding for postgraduate research in formulation, physical pharmacy and pharmaceutical technology/engineering — nowadays, such funding is associated with departments of chemical or mechanical engineering — and pharmacy departments at universities are suffering the consequences. They can no longer recruit academic staff capable of teaching these specialist topics. The teaching of pharmaceutics is, hence, often reduced to 'advanced drug delivery', such as liposomes and nanoparticles. Many new departments, and even some of the established pharmacy schools, lack basic technology equipment such as granulators, mixers and tabletting machines. 

Under the 1946 National Health Services Act, pharmacists were given the explicit role of supplying all medicines and appliances prescribed. This brief requires the maintenance of the unique skills of formulation and manufacture of medicines, but the profession is now moving away from this. Pharmacists are encouraged to respond to symptoms and prescribe, and the knowledge of medicine making is no longer of interest. Thus, pharmacists are giving up their unique skills for access to clinical work that can be done by a number of professions. 

Unfortunately, the pharmaceutical industry appears ready to support this trend. In a recent article,

  it was suggested that the future roles of pharmacists in the pharmaceutical industry included mainly clinical (e.g., medical information, pharmacovigilance, regulatory affairs and clinical research) and marketing skills rather than technical skills. The author admitted that for the latter, the industry has opted for the wider choice of recruits from all areas of science and engineering. 

On an annual basis, representatives from the pharmaceutical industry visit the UK's schools and departments of pharmacy. These visits have different shapes and sizes, ranging from an afternoon of plenary lectures to informal meetings with individual students. In this way, the pharmaceutical industry is attempting to raise its profile among pharmacy undergraduate students. The message repeatedly received by students is that there are only a few industrial preregistration places available in the UK, and that these are reserved for students from a select few 'established' schools of pharmacy. Any pharmacist wishing to join the pharmaceutical industry without having had such a preregistration place or a PhD in a relevant field of research is expected to work for a few years in community pharmacies or hospitals before approaching recruitment agencies. The question that arises here is whether and how the pharmaceutical industry is approaching young pharmacists that have spent time in community or hospital pharmacies.

Finally, current developments in the perceptions of the role of pharmacists in the society at large are not only disadvantageous for the pharmaceutical industry and academia, but also for patients. Prescription errors, and errors in handling and taking of medicines are, sadly, rather common. For example, delayed and modified release tablets are frequently crushed to ease swallowing, yet pharmacists do not normally advise patients who are collecting their prescriptions not to do so; usually the pharmacist checks the name of the patient and otherwise remains silent. In a way, one might feel sorry for the pharmacists — how are they to recognise such a medicine if their formulation and technology training was limited? 

is affiliated with University College London (UK).

Last year, the Royal Pharmaceutical Society of Great Britain held a consultation regarding how the profession should develop during the next 12 years. An analysis of the results has just been published.1 It comes as no surprise to anyone who teaches pharmaceutics at UK pharmacy departments that one popular suggestion was to change the indicative syllabus so that it would focus more on clinical topics as opposed to scientific ones.

Pharmaceutics teaching and the pharmaceutical industry

  we have shown that it is possible to incorporate the glyceride, glycerly monostearate (GMS), into pellet formulations at a level of at least 30% and still produce round pellets, without reducing the 

 drug release. The formulations required less water than those containing microcrystalline cellulose (MCC) alone as the spheronization aid, which appears to be the reason for the improved stability of formulations containing ranitadine hydrochloride.

The inclusion of GMS also offers the opportunity to incorporate drugs that are water insoluble or are poorly permeable through the gastrointestinal membrane into the nonaqueous phase of the formulation. 

 Table 1.  Formulation codes for the additives to the standard formulation of 10% diclofenac sodium, 30% additive, with the remainder of the formulation being MCC.			

GMS is not a pure material — even the Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP) and the United States National Formulary (USNF) differ in their standards.

  The question arises, therefore, do these allowable differences change the performance of the products, and would other types of glycerides used in pharmaceutical formulations (e.g., as absorption enhancers) perform in the same way? To investigate these issues, we have used a previously reported successful formulation that contained a model drug (10% diclofenac sodium) with a range of glycerides as an additive (30%), MCC (60% ) and water. As a comparison, a formulation containing 10% drug with 90% MCC is reported as a standard. The glycerides are glyceryl monostearate of differing composition; a mixture of mono and diglycerides; and hydrogenated natural oil glycerides. 

 GMS (lot number 209215; Huls [UK] Ltd), containing 40–50% GMS, melting range of 57–59 °C, EP grade.   

  Imwitor 900 (Huls) containing 40–50% monoglycerides with a melting range of 56–61 °C.   

  Imwitor 191 (Huls) containing a minimum of 90% monoglycerides, mainly GMS and glyceryl monopalmitate, melting range of 66–71 °C.   

  Imwitor 742 is described as a medium chain (caprylic/capric) partial glyceride with a minimum monoglyceride content of 45%, melting range of 22–27 °C.  

  Glycerol esters of hydrogenated coglycerides (Softisan 142), with a melting range of 42–44 °C, and hydrogenated palm oil (Softisan 154), with a melting range of 53–58 °C, were also supplied by Huls. 

The GMS and Imwitor 900 were ground in a small coffee grinder (Bruan AG, Germany) and passed through a 250 μm aperture sieve. The Softisans were again ground in the coffee grinder, but a 500 μm aperture sieve was used because of the greater difficulty in grinding the softer materials. Imwitor 191 and 742 were used as received. Imwitor 724 was soft enough to be incorporated directly into the powder when preparing the wet powder mass. 

MCC was Avicel PH101 (batch 6521; FMC International, Ireland). The model drug (diclofenac sodium) was purchased from Profarma Nobel (Sweden) and had a mean Feret's number diameter of 58.4 μm. 

The materials were combined in the ratio 10% drug, 30% additive and 60% MCC, and given the formulation code set out in Table 1. Where no additive is recorded, the MCC content was increased to 90%. 

Table 2 .  Particle size, apparent particle density and contact angle of the materials used in the pellet formulations (values Â± standard deviation).			

The particle size of the materials tested in the formulations was determined by an image analyser (Seescan Solitaire 512; Seescan, UK), connected to a black and white camera (CCD-4 miniature video camera; Rengo Co. Ltd, Japan) and an Olympus BH-2 microscope (Olympus, Japan), set at a suitable magnification to the size of the particles being measured. The Feret diameter, a mean distance between two parallel tangents (obtained from 36 measurements around a particle in 10 ° increments) of 500 particles, was obtained and the number average particle size was determined from Edmonson's equation 4 (Table 2). The apparent particle density of the raw materials and the apparent pellet density were determined with an air comparison pycnometer (Model 930; Beckman, USA) using ambient air. Three volume measurements of known sample weights were made and the values for the raw materials given in Table 2.   

Table 3 . The quantity of water required, extrusion force and type of flow for various formulations extruded under standard conditions.			

The value for the contact angles of water on the glycerides was determined with a Cahn dynamic contact angle analyser (Cahn Instruments, USA) using the Wilhemly plate method.

  Plates of the materials were prepared by compacting rectangular samples of the powders in a specially prepared punch and die set (20 mm×20 mm) using a Specac hydraulic press (Specac Ltd, Kent, UK).  

For Imwitor 724, a glass plate was covered with the material by immersing it in a molten sample of the material and cooling slowly at room temperature. The perimeter of each plate was measured with a micrometer+10 μm. The water used was freshly prepared distilled and the values in Table 2 are the mean of five sample plates.  

The pellets were prepared by first mixing the powders in a planetary mixer, adding the water, extruding the wet mass at 200 mm/min through a 1 mm diameter die attached to a 2.54 cm diameter barrel of a ram extruder, followed by spheronization on a 12 cm diameter crosshatched plate (Caleva, UK), rotating at 1800 rpm for 10?min. The full details of the whole process have been described previously.

  The pellets, except those containing Imwitor 742, were dried at 40 °C for 14 h in a hot air oven (Pickstone Ltd, UK). Pellets containing Imwitor 742 were allowed to dry at room temperature until a constant weight was achieved. This usually took 48 h. 

The particle size of the pellets was determined by sieve analysis using a set of British Standard sieves in a square root 2 progression of sieve sizes, with the introduction of a 1700 μm sieve between the 1400 μm and 2000 μm sieves to provide a more detailed analysis. From the cumulative per cent undersize graph, the median and the interquartile range of the size distribution were obtained, while the mode and the percentage of pellets in the modal size were obtained from the sieve analysis. The shape factor (eR) was obtained

  by the same image analyser used to determine the particle size of the powders. The porosity of the pellets was obtained as 1 minus the ratio of the apparent pellet density to the apparent particle density of the powdered components of the pellets. 

The drug release from the pellets was assessed by USPXXXI dissolution apparatus II or paddle method (Pharmatest Dissolution Tester, Type PTWS, Germany), with a paddle speed of 100 rpm in 900?mL of simulated intestinal fluid (without pancreatin) at pH 7.5, with the quantity of pellets chosen to ensure that sink conditions were attained. The quantity of diclofenac in the samples, which were taken automatically at known time intervals, was analysed by UV spectrophotometry (UV-Vis spectrophotometer Model 554; Bodenseewerk Perkin-Elmer & Co. GmbH, Germany). Six beakers were used for each pellet formulation.  

The water level in 60% of the dry solid content, which had been shown to be suitable for the GMS preparation G01,

  was selected as the starting point for the other glycerides. It was found to be appropriate for the range of other glycerides, except for the Imwitor 742. Here, the water required to provide a smooth extrudate and round pellets with a narrow size distribution had to be reduced to just 16% (Table 3). This glyceride has the lowest melting range and would be the most deformable of the glycerides, although with the level of water added, it required the greatest force to extrude the mass. In all cases, the extrudate was completely smooth and the extrusion displacement gave a constant steady state extrusion force.  

Table 4 Particle size characteristics of the pellets produced from the various formulations.			

All the extrudates from the different formulations rounded to form pellets within the 10 min of the spheronization process. The modal size fraction, the percentage in this fraction, the median size and the interquartile range show that there is a good uniformity in the pellets produced from the different formulations (Table 4). In particular, the three types of GMS produce pellets that are very similar and thus the differences in the types is not important to their function. As observed previously, the size is larger than pellets prepared with just MCC. The two hydrogenated glycerides, Softisan 142 and 154, produce pellets that are very similar in size and size distribution, but the inclusion of Imwitior 742 produces larger pellets with a similar size range.  

Figure 1 The MDT as a function of the contact angle of the glyceride (linear correlation coefficient r = -0.843)			

When the shape of the pellets is considered, it is clear that all the various formulations produce pellets that are acceptably spherical — eR values greater than 0.58 and aspect ratios less than 1.01 (Table 5). The least round pellets were those containing Imwitor 742, which had the highest extrusion force and the largest pellet size. The porosity of the pellets varied with the formulation. The highest porosity was for the grade of GMS containing 40–50% GMS, which would have been expected to be very similar to batch G01. The source of this difference is difficult to explain as pellets containing these two grades were very similar in all other respects. The pellets with the lowest value for porosity were prepared from the formulation containing Imwitor 742, the material that showed the greatest differences in other properties. 

Table 5 Shape factor eR, aspect ratio, apparent pellet density and porosity of pellets prepared form the various formulations (mean values Â±standard deviations; n=50 for eR and aspect ratio; n=3 for apparent pellets density and porosity).			

 drug release, characterized by the use of statistical moments,

  is presented in Table 6. All formulations containing the various glcyerides release the drug faster than the formulation containing only MCC and drug. There appears to be no consistent release mechanism controlling the process, which is perhaps not surprising as the time period is relatively short — representing an immediate release rather than an extend release profile. Also, in the case of all the pellets containing the various glycerides, fracturing of the surface during the dissolution test was observed, indicating that there was not a constant surface area from which the dissolution occurred 

It is difficult to represent the physical properties of the glycerides to be able to relate their properties to those of the pellets. As they are all relatively hydrophobic, the contact angle may be a suitable measure. When the formulation/pellet properties of quantity of water required, mean steady state extrusion force, median pellet diameter and pellet porosity were plotted as a function of the contact angle, none of the graphs indicated a potential relationship. When, however, the mean dissolution time (MDT) was plotted as a function of the contact angle, there was a clear indication that the value of the contact angle increased as the value of MDT decreased (Figure 1). This appears contradictory, but implies that the presence of the hydrophobic material does not inhibit ingress of fluid into the pellet and in fact appears to assist the ingress of active fluid. The aqueous fluid that penetrates the MCC appears to be held firmly and delays the release of the drug from the pellet structure.   

Table 6 Dissolution characteristics of the various pellet formulations. MDT; variance associated with the MDT; relative dispersion of the dissolution time (RD) and the release model of the drug release from the pellets, 1, first order; 2, square root; N, no simple kinetics. The pellet size was the 1400Ã¢ÂÂ1700 Î¼m size fraction and the values are the mean 6 the standard deviations of Â± replicates.			

The results show that variability in the type of GMS does not alter the ability of this additive to perform its function as an enhancer of pellet formation by extrusion/spheronization. For three different types, the water level required to provide smooth regular extrudate at equivalent extrusion forces, which readily form spherical pellets, was the same and is considerably less than that required with MCC alone. The only difference in performance was that one batch of the GMS (Imwitor 191) produced pellets that were more porous, but the size, shape and drug release performance was the same. It was possible to replace the GMS with hydrogenated glycerides and retain the pellet performance. All these formulations offer the opportunity to reduce the water required to form the pellets, which may have implications for the stability of some drugs. The replacement of the GMS with Imwitor 742 allowed an even further reduction in the quantity of water required for pellet formation. The fastest drug release was obtained with the additive Softisan?142, which was the most hydrophobic, having the highest value for the contact angle against water.  

Thus, pharmaceutically acceptable glycerides provide an additional option when it comes to the formulation of pellets by extrusion/spheronization. 

1. J. Chatchawalsaisin, F. Podczeck and J.M. Newton, 

2. A.W. Basit, J.M. Newton and L.F. Lacey, 

3. R.C. Rowe, P.J. Sheskey and P.J. Weller, 

(Pharmaceutical Press, London, UK, 2003). 

4. I.C. Edmonson, "Particle Size Analysis" in H.S. Bean 

Advances in Pharmaceutical Sciences Volume 2

	(Academic Press, London, UK, 1967) pp 95–179. 

 (Oxford University Press, London, UK, 1949) pp 490–492. 

8. D.Veogle, D.Brockmeier and H.M. von Hattingberg, "Modelling of Input Function to Drug Absorption by Moments," Proceedings of the Symposium on Compartmental 

and Non-Compartmental Modelling in Pharmacokinetics" (Smolenice, The Czeck Republic, 12–16 September 1994) pp1–14. 

9. S. Boutel, "Factors Influencing the Preparation of Spherical Granules by Extrusion/Spheronization," PhD Thesis University of London, London, UK (1995).  

The previous studies on the incorporation of glyceryl monostearate into pellets by extrusion/spheronization has been extended to include a range of grades of this material plus a mixed medium chain partial glyceride and two glycerol esters of hydrogenated natural glycerides as described in this article.

The influence of monoglycerides, mixtures and derivatives on the formation of pellets by extrusion/spheronization

The process of preparing spherical granules of approximately 1 mm in diameter by extrusion/ spheronization was introduced during the late 1960s. It involves forming the powder into a wet mass, which is forced through a restricted area (extrusion) to form strands of extrudate that are broken into short lengths and rounded by placement on a rotating plate within a cylinder.

 		 The sequence associated with the rounding of the extrudate have been described by Chapman.

The exact consistency required to ensure that a wet mass can be processed into pellets is difficult to define. Raines 

 to establish a relationship between measurable rheological parameters obtained by utilization of a ram extruder and the quality of the surface of extrudate.

 Chohan and Newton have demonstrated that the same formulations also show the presence of extensional flow and elasticity.

 have demonstrated that measurements of the storage and loss modulus values of formulations may provide an insight into the evaluation of the rheological properties of wet powder masses that can be processed to form acceptable round pellets.

 Certainly, simple shear rate/shear stress graphs cannot adequately define the rheolgical properties of the paste that can be successfully processed, but simple extrusion force measurements provide a guide to formulation suitability.  

Most formulations used in the pharmaceutical industry contain microcrystalline cellulose (MCC), which is capable of holding water rather like a sponge and restricting the separation of water from the solid that can occur during extrusion and spheronization.

 There are literature claims that other excipients can be used to replace MCC. These claims are often over optimistic and are based on a less than objective assessment of the quality of the pellets. For example, a recent paper claims that pectinic acid is "well suited as an excipient for pelletization by extrusion/spheronization."

 The results clearly show that pellets can be prepared from a range of contents of pectinic acid and lactose, but the quality of the pellets formed must be questioned as none of the so-called optimum formulations form pellets that can be described as spherical. Even by the insensitive method of describing "roundness," namely the aspect ratio, none of the formulations reported has a value for the aspect ratio of less than 1.10, which is far from a spherical pellet.  			

Several of the so-called "optimum" formulations have an aspect ratio of approximately 1.20, the value shown by Chopra 

 to be the limiting value for satisfactory filling of pellets into capsules.

 In addition to the lack of roundness, extrusion/spheronization is such that as the pellets become less round, there can also be an increase in shape variation. For example, if the results of Chopra are considered, for pellets that were intentionally made with different shapes, the variation coefficient of the aspect ratio (1.06) for the "spheronized" pellets was 3.37%, whereas that for the "long dumbbells" (aspect ratio, 1.59) was 10.69%.

 Thus, as a general principle, as pellets become less round, there is the tendency to become more variable in shape.  

There are circumstances when the presence of MCC can be detrimental to a formulation. Basit 

found that, for a specific formulation containing the drug ranitidine, the decomposition of the drug could be restricted to acceptable levels if the quantity of MCC was reduced and glyceryl monostearate (GMS) was added to the formulation.

 The aim of this work was to determine if this was just a solution to a specific problem and whether it was possible to totally remove MCC from formulations. 

Barium sulfate (batch 5/093/3) was supplied by Sachtleben Chemie GmbH (Germany), grade XRHN with a particle size grade of 10 μm. GMS (batch 209215, mean Feret's number diameter 59.l μm), was provided by Huls (UK) as 

. Diclofenac sodium (batch 0703, mean Feret's number diameter 20.0 μm) was purchased from Profarma Nobel (Sweden). The MCC (mean Feret's number diameter of 54.8 μm) was 

 (batch 6521, FMC International [Ireland]). The compositions of the formulations tested are presented in Table I. The quantity of water required was obtained by trial and error to provide a formulation which, generally, could be extruded and spheronized to give pellets of uniform size and shape. 

Table I Composition of formulations.						

To produce the pellets, the powders were dry blended for 5 min in a planetary mixer (Kenwood Chef, UK). The required amount of water, which was obtained by initial ranging experiments, was added and the mixing continued for a further 10 min with occasional scraping of the sides of the bowl. The weight mass was packed into a ram extruder, which was fitted with a die of diameter 1.5 and length 6 mm.

 The ram of the extruder was driven downwards within the barrel at 200 mm/min by a mechanical press (

; Lloyds, UK). The force resisting flow/piston displacement graph was recorded using a computer; the type of flow and, where appropriate, the value of the steady state flow has recorded (3 determinations). The extrudate (100 g) was spheronized on a 12.5 cm diameter spheronizer fitted with a crosshatch plate (Caleva, UK) rotating at 1800 rpm for 10 min. The pellets were dried in a hot air oven (Pickstone Equipment, UK) at 40 °C for 12 h. 

The particle size distribution of the pellets was determined by sieve analysis using a set of British Standard Sieves (BSS 450) and an agitator (Endecotts, UK). From a cumulative percentage undersize graph, the median size and the inter quartile range were estimated. The shape of the pellets (sample size, 100 pellets) in the most frequently occurring size fraction was assessed as a two-dimensional shape factor e

; Sonata, UK) connected to a black and white camera (

 miniature video camera module; Rengo Co. Ltd, Japan) and zoom lens (

; Olympus, Germany). The magnification was set so that one pixel was less than 26 μm

 for each formulation measured. The apparent density of the pellets taken from the median size fraction was determined (3 replicate determinations) with an air comparison pycnometer (

; Beckman Irwin, USA). The porosity was obtained as 1 minus the ratio of the apparent pellet density to the apparent powder density of the constituents of the pellets. 			

Dissolution of the pellets containing diclofenac sodium was undertaken with the USP XXXI dissolution apparatus II or paddle method (Pharmatest Dissolution tester, Type PTWS, Germany), with a paddle speed of 100 rpm in 900 mL of simulated intestinal fluid, without pancreatin. A pH of 7.5 was achieved with a buffer containing, 0.05 M monobasic potassium phosphate and 0.038 M sodium hydroxide, with a total ionic strength of 0.088 M. The quantity of pellets, from the modal size fraction, was chosen to ensure that sink conditions were maintained. The quantity of drug present in the samples automatically taken at known time intervals was analysed by UV spectrophotometry (

; Bodenseewerk Perkin-Elmer & Co. GmbH, Germany). Six beakers were used for each formulation.  

 The two model materials tested represent drugs with a very low solubility 0.0025 g/L (barium sulfate) and one with low solubility 9 g/L (diclofenac sodium). The formulations incorporated as much as 90% of the two model drugs. That it was possible to prepare pellets from the formulations listed in Table I illustrates the potential of GMS as an excipient, which can provide the possibility of preparing spherical granules for different materials. To compare the performance of the GMS, one formulation of each of the model drugs was prepared with MCC. It is clearly noticeable that the quantity of water required to be able to prepare the formulations containing MCC is approximately double that required to prepare pellets with GMS. 						

Within the GMS formulations, the amount of water required decreased as the quantity of GMS increased when diclofenac was the model compound. The quantity of water was slightly reduced in the case of the barium sulfate when the level of GMS increased. This shows that the components of the formulation have an important influence on the level of water needed to allow the process to be successful. The formulations all required similar levels of steady state extrusion force and these represent the levels often encountered with conventional formulations containing MCC (Table II). At less than 4 kN, the extrudate is often too soft and tends to agglomerate when placed on the spheronizer plate, and at more than 20 kN the extrudate fails to round even after prolonged spheronization. All the extrudates had a smooth surface and there was no evidence of surface irregularities of the type reported by Harrison 

Table II Characteristics of the extrusion process.			

 The pellets containing GMS tend to have a median diameter larger than the die diameter (1.5 mm), whereas those containing MCC are slightly smaller (Table III). For diclofenac, the diameter increases as the quantity of drug increases. If the process described by Chapman forms the spherical granules, the final diameter can be greater than the extrudate diameter if, prior to spheronization, the extrudate breaks into sections that are considerably longer than its diameter.

Table III Characteristics of the pellets produced by the formulations.			

The degree of consolidation, which occurs during the process, is clearly shown by the final porosity of the pellets. The very low levels of porosity obtained with pellets containing high levels of GMS and diclofenac (0.04-0.09) contrast with those that contain the high levels of barium sulfate (0.25-0.30). A comparison of the formulations containing GMS and MCC shows that for barium sulphate formulations, the porosity is lower with MCC, whereas it is the reverse for the diclofenac formulations. There is clearly a difference in structure of the granules despite the apparent similarity of processing. 			

 The shape of pellets prepared from diclofenac is nearly round because the value of e

 for ball bearings of this diameter is 0.7. The values for e

 of the highest levels of barium sulfate are not quite as satisfactory as the other pellets, but an e

 of 0.523 presents pellets that are nearly spherical. The aspect ratios of all the pellets are well within the acceptability limiting value for capsule filling suggested by Chopra.

 If anything, the pellets containing GMS have slightly higher values for roundness measure.  

 Pellet dissolution results (Figure 1) were analysed by the statistical moment theory.

 The drug release for two formulations containing 10% of drug was faster from the formulation prepared with MCC. In fact the formulation containing 90% GMS had the highest value for the mean dissolution time (MDT). This is perhaps not too surprising in view of the hydrophobic nature of GMS. The 1.04 h value of MDT does not make this a controlled release formulation. As the level of drug increases and that of GMS decreases, the value of the MDT fluctuates, but even at a 50% drug load, the formulation has a value of MDT comparable with preparations that contain 20% and 50% drug.  

Figure 1 In vitro dissolution of diclofenac pellet formulations.			

The 10% and 40% drug containing formulations, show a release mechanism represented by the square root law; that is, diffusion controlled release. The 10% and 40% are two of the slowest releasing formulations. A further factor involved with the release mechanism is the pellets' dimensions. For pellets containing 10, 20 and 30% of drug the model size fraction used in the test was 1700-2000 μm; for 40% the pellets were 2000-2360 μm; and for 50% the size fraction was 2360-2800 μm. The dimensions involved in the penetration of fluid into the pellet and the transfer of the drug out of the pellets differed, altering the mechanism of drug release observed. 

The work has demonstrated that it is possible to prepare spherical granules by extrusion/spheronization without MCC. This can be achieved by adding GMS at levels ranging from 10-90%. The granules have a larger diameter than the dimensions used to produce the extrudate, but in all cases were acceptably spherical. The structure of the granules as represented by the porosity is dependent on the quantity of GMS present and the properties of the additional material. For high concentrations of GMS porosity levels less than 10% can be achieved.  

Table IV Dissolution performance of pellets in the modal size fraction: as area under the dissolution time profile (AUC), mean dissolution time (MDT), relative dispersion (RD) of the dissolution time (VR) and the release model (RM).						

When compared with formulations containing the same quantities of model drug and MCC, those containing GMS required less than half the quantity of water, yet had similar extrusion force/displacement profiles. The pellets from the GMS formulations always produced pellets that were larger. The drug release from GMS formulations was at a slightly reduced rate than those containing MCC, but as the drug content of the pellets increased, the release rate generally increased. The release rates from GMS formulations were nearer to an immediate release formulation than an extended release formulation. Thus, GMS can be considered as a spheronization enhancer rather than a controlled release additive. 

1. A.D. Reynolds, "A New Technique for the Production of Spherical Particles," 

2. S.R. Chapman, "Influence of Process Variables on the Production of Spherical Particles," PhD Thesis, University of London, London, UK (1985). 

3. C.L. Raines, J.M. Newton and R.C. Rowe, "Extrusion of Microcrystalline Cellulose Formulations," in R.F. Carter, Ed., 

Rheology of Food, Pharmaceuticals and Biological Materials and General Rheology

 (Elsevier Applied Science, London, UK, 1990) pp 248 —257. 

4. J.J. Benbow, E.W. Oxley and J. Bridgewater, "The Extrusion Mechanism of Pastes— the Influence of Paste Formulation on Extrusion Parameters," 

5. R.K. Chohan and J.M. Newton, "Analysis of Extrusion of Some Wet Powder Masses Used in Extrusion/Spheronization," 

6. K.A. MacRitchie, J.M. Newton and R.C. Rowe, "The Evaluation of the Rheological Properties of Lactose/Microcrystalline Cellulose and Water Mixtures by Controlled Stress Rhoemetry and the Relationship to the Production of Spherical Pellets by Extrusion/Spheronzation," 

., "Thermal Studies on the Interaction of Water and Microcrystalline Cellulose," 

., "A Comparison Between the Extrusion Forces and Sphere Quality of a Gravity Feed Extruder and a Ram Extruder," 

9. I. Tho, S.A. Sande and P. Kleinebudde, "Pectinic Acid, A Novel Excipient for the Production of Pellets by Extrusion/ Spheronization: Preliminary Studies," 

., "The Influence of Pellet Shape and Film Coating on the Filling of Pellets into Hard Shell Capsules," 

11.  A.W. Basit, J.M. Newton and L.F. Lacey, "Formulation of Ranitidine Pellets by Extrusion-Spheronization with Little or No Microcrystalline Cellulose," 

12. A. Ovenston and J.J. Benbow, "Effects of Die Geometry on Extrusion of Clay Like Materials," 

13. F. Podczeck and J.M.Newton, "A Shape Factor to Characterize the Quality of Spheroids," 

14. P.J. Harrison, J.M. Newton and R.C. Rowe, "Flow Defects in Wet Powder Mass Extrusion," 

15. D. Voegle, D. Brockmeier and H.M. von Hattingberg, "Modelling of Input Function to Drug Absorption by Moments," in 

Proceedings of the Symposium on Compartmental and Non-Compartmental Modelling in Pharmacokinetics

 (Smolenice, The Czech Republic, 12—16 September 1994) pp 1 — 14.

The process of extrusion/spheronization used to produce spherical granules frequently relies on formulations containing microcrystalline cellulose (MCC). This excipient can hold water, even when pressure is applied, and form "pastes" that have suitable rheological properties, which allow both extrusion and subsequent spheronization to produce uniform spherical granules. This article describes a new approach to providing paste systems with appropriate characteristics. This can be achieved by incorporating glyceryl monostearate (GMS) into the formulation. It was found that the inclusion of GMS in formulations provides a useful alternative to MCC as an effective excipient to aid the preparation of spherical granules, allowing the incorporation of drug loads as high as 90%.