#T2278

Preparation of esomeprazole magnesium pellets by extrusion spheronization

J. Balasubramaniam, Y.V. Rajesh, K. Bindu, B.C. Ratnam, J. Yang, T. Bee and S. Porter

ABSTRACT
In this preliminary study, multiparticulate pellets containing esomeprazole magnesium have been prepared using an extrusion spheronization process, employing povidone and crospovidone as non-traditional processing aids. Attempts have been made to prepare pellets of various sizes and ultimately investigate the levels of enteric coating that need to be applied in order to achieve a suitable delayed-release dissolution profile. While acceptable pellets, displaying appropriate drug delayed-release characteristics have been achieved, it is evident from this initial study that further formulation and processing refinements, with respect to the formation of the initial pellets, need to be made in order to create pellets with optimal sphericity characteristics and narrower particle size distributions.

Passing the wet-granulated mass through the extruder, and spheronizing the extrudate, using the Umang Pharmatech Extruder/Spheronizer. Drying the pellets using a tray oven drier. Sieving the resultant dried pellets to obtain a range of separate pellet sizes from 0.5 to 1.5 mm.

Conditions used in preparation of pellets by extrusion spheronization

Parameter
Batch size (kg) Extruder screen opening (mm) Extruder speed (rpm) Spheronizing time (s) Spheronizer speed (rpm) Spheronizer plate

Set point
1.0 0.5 100 20 2800 1.0

OBJECTIVE
To conduct a preliminary investigation into preparing pellets containing esomeprazole magnesium by means of an extrusion spheronization process, using povidone as the primary binding agent and crospovidone as the processing aid. In addition, to determine the appropriate levels of enteric coating needed to create a suitable delayed-release product.

EXPERIMENTAL METHODS
A preliminary study was set up to determine general formulation and processing parameters needed to prepare pellets using the extrusion spheronization process. Ultimately, further evaluations were made to facilitate improvements in both the formulations used and the processing conditions employed. Preliminary study Preparation of pellets: The formulation used in the preparation of the pellets is shown in the following Table.
Ingredient
Esomeprazole magnesium Sodium carbonate Mannitol (Mannogem EZ) Crospovidone (Polyplasdone XL-10) Povidone (Plasdone K-29/32)

Coating of pellets: The resultant pellets were coated using an Aeromatic Strea-1 fluid-bed machine fitted with a 6 Wurster insert. The pellets were initially sealed with a clear HPMC-based water-soluble coating (Advantia Prime 199989HA09), and then subsequently enteric coated using an acrylic entericcoating formulation (Advantia Performance 190024HA49). In each case, the level of coating applied was adjusted to take into account the variation in size of the starting pellets. The details of the coating procedures are summarized in the Table below. Dissolution testing: Evaluation of drug release characteristics was achieved using USP Apparatus 1. All samples were initially exposed for two hours in 0.1 N HCl solution, followed by one hour in buffer solution, pH=6.8. Summary of conditions used for coating pellets
Process parameter
Initial pellet charge (kg) Inlet temperature (C) Product temperature (C) Exhaust temperature (C) Atomizing air pressure (bar) Process air flap setting (%) Coating solids (% w/w) Spray rate (g min -1) Target weight gain (% w/w)
*

Quantity used (% w/w)

30.7 6.8 29.1 30.7 2.7

Specific process conditions Subcoating

60 40-45 40-50 1.0 10 10 5 6, 10, or 15*

Enteric coating
0.5 50 37-42 35-40 1.0 12 20 4 15, 20, or 25*

General procedures: The preparation of the pellets involved: Preparing the initial granulation, using a Pro-C-Ept granulator in which the dry ingredients were blended prior to the addition of the requisite quantity of water.

Quantity depends on starting size of pellets, which were 0.5, 1.0, or 1.5 mm respectively

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Follow-up study The preliminary study to examine the use of non-traditional excipients in the preparation of pellets using the extrusion spheronization process, while clearly demonstrating the potential for using such excipients in this type of process, ultimately did not yield ideal pellets in terms of both particle size and particle shape. As a follow up, an attempt has been made to achieve measurable improvements in both of these aspects of pellet characteristics. Once prepared, the pellets were subsequently enteric coated using a similar approach as that used in the initial study. Preparation of pellets: In contrast to the initial study, a modified formulation (see Table below) was used, primarily to eliminate the influence of sodium carbonate on the pellet spheronizing characteristics. The general process used in preparing the pellets involved: Preparing the initial granulation using a planetary mixer, whereby all powder materials (premixed for 5 minutes in a plastic bag) where granulated after the addition of a fixed quantity of water. Extruding the granulated mass through a NICA extruder. Spheronizing the extrudate using a NICA spheronizer. Drying the subsequent pellets using an Aeromatic Strea-1 fluid-bed drier.

RESULTS
Preliminary study As a first step, the results obtained were sufficient to lend validity to the approaches taken in this study. Acceptable pellets were obtained by means of extrusion spheronization and satisfactory delayed-release characteristics after the pellets had been coated. Photomicrographs and scanning electron micrographs of pellets, after enteric coating, are shown below. Since the pellets were initially obtained using a fixed screen size in the extruder, and the different particle sizes (for further evaluation) were obtained using a sieving technique, it is quite evident from the images shown that the larger particle size fractions are more represented by particles that still retained more of their cylindrical shape, or had perhaps grown through agglomeration. Photomicrographs of coated pellets obtained

Formulation used to prepare pellets

Ingredient
Esomeprazole magnesium Mannitol Crospovidone Povidone (K-29/32)
(Note: 420 g of purified water was added to 1000 g of powder)

Quantity used (% w/w)

30.7 34.9 30.7 3.7

(a) 0.5 mm Pellets

(b) 1.0 mm Pellets

(c) 1.5 mm Pellets

Scanning electron micrographs of coated pellets

Coating of pellets: Esomeprazole pellets were subsequently enteric coated using a Uni-Glatt fluid-bed coater fitted with a 6 Wurster insert and employing the coating process conditions shown in the table below. Summary of conditions used to coat pellets in Uni-Glatt Wurster process
Process parameter
Initial pellet charge (g) Flap setting (%) Inlet temperature (C) Exhaust temperature (C) Coating system Coating Solids (% w/w) Spray rate (g min -1) Target weight gain (% w/w)

(a) 0.5 mm Pellets

(b) 1.0 mm Pellets

(c) 1.5 mm Pellets

Dissolution results, obtained for enteric-coated esomeprazole pellets of each of the three size fractions are shown below. Dissolution results obtained for esomeprazole magnesium enteric-coated pellets (first 2 hours in 0.1N HCl solution, followed by 1 hour in buffer pH=6.8)
0.5 mm Pellets Percent Drug Dissolved
120 100 80 60 40 20 0 0 60 120 180

Process set points Subcoating Enteric coating

900 20 62 41 Advantia Prime 199989HA09 12 8.4 3.0 20 60 40 Advantia Performance 285989HA49 20 15 15.0

Dissolution testing of enteric-coated pellets: Dissolution testing was carried out using USP Apparatus 1. All samples were initially exposed for two hours in 0.1 N HCl solution, followed by one hour in buffer solution, pH=6.8.

Time (min)

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1.0 mm Pellets Percent Drug Dissolved

120 100 80 60 40 20 0 0 60 120 180

The characteristics of the pellets, after subsequent subcoating and enteric coating, are shown below. Photomicrographs of coated pellets

Time (min) 1.5 mm Pellets Percent Drug Dissolved

120 100 80 60 40 20 0 0 60 120 180
(a) Subcoated pellets (b) Enteric coated pellets

While these coated samples are generally acceptable, some degree of agglomeration was observed. Consequently, further optimization of the coating process conditions is clearly warranted. In terms of drug-release characteristics, the data shown in the figure below indicate that again, while acceptable results were achieved, further process optimization, especially in terms of defining the ideal level of applied coating, is indicated. This will be the focus of ongoing studies. Drug release characteristics for enteric-coated esomeprazole Mg pellets
120

Time (min)

Percent durg dissolved

Acceptable delayed release dissolution results were achieved in each case, with a maximum of approximately 5% drug being released in 0.1 N HCl solution after two hours, and 100% drug being released within 1 hour after exposure to buffer pH=6.8. Follow-up study The process conditions employed in this phase of the work achieved a significant improvement in pellet characteristics, both in terms of sphericity and particle size distribution (see Figures below).
Photomicrograph of uncoated pellets

100 80 60 40 20 0 0 20 40 60 80 100 120 140 160 180 200

Time (min)

100.0%

Weight percentage

80.0% 60.0% 40.0% 20.0% 0.0% 0 10 20 30 40 Mesh size 50 60 70

Particle size distribution of uncoated pellets

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CONCLUSIONS
This study has demonstrated that the use of povidone (as a binder) and crospovidone (as a processing aid) are viable options for producing pellets using the extrusion spheronization process. Clearly, however, this work represents only a starting point, as opportunities for further formulation and process optimization are evident from the results obtained. Paramount among these options is the need, inter alia, to: Optimize the formulations and processing conditions for preparing pellets using the extrusion spheronization process. Investigate, in particular, the influence of modifying the drug content in the formulation and the quantity of processing aid used. Compare potential results obtained with those that are typically achieved using more traditional extrusion spheronization processing aids (such as microcrystalline cellulose). Optimize the process for subsequent application of both the subcoating and the enteric coatings used as a means of achieving both appropriate product stability and effective drug release characteristics.

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