How to step-up metformin tablets production from a pilot scale coater to three different industrial scale equipment.

Authors Caterina Funaro, Process R&D Laboratory Manager at IMA Active Massimo Malavolti, Product Manager for coating equipment at IMA Active

1. Introduction

The discovery of metformin began with the synthesis of galegine-like compounds derived from Gallega officinalis, a plant traditionally employed in Europe as a drug for diabetes treatment for centuries. Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle. Metformin’s efficacy, security profile, benefic cardiovascular and metabolic effects, and its capacity to be associated with other antidiabetic agents makes this drug the first glucose lowering agent of choice when treating patients with type 2 diabetes mellitus.
Thus far, metformin is the only antidiabetic agent which has shown reduced macrovascular outcomes which is likely explained by its effects beyond glycemic control. It has also been employed as an adjunct to lifestyle modifications in pre-diabetes and insulinresistant states. Although monotherapy with an oral hypoglycemic agent is often initially effective, glycemic control deteriorates in most patients which requires the addition of a second agent.
Gastrointestinal side-effects are common with the use of metformin of standard release and are usually associated with rapid titration and high-dose initiation of metformin. These effects are generally transient, arise early in the course of treatment, and tend to subside over time. The gastrointestinal side-effects can be addressed by taking the agent with meals, reducing the rate of dose escalation, or transferring to a prolongedrelease formulation (XR).
The metformin XR formulation releases the active drug through hydrated polymers which expand after uptake of fluid, prolonging gastric residence time which leads to slower drug absorption in the upper gastrointestinal tract and allows once-daily administration.
Metformin XR has been associated with improved tolerability and increased compliance.
A large proportion of metformin tablets (either IR or XR formulations) produced globally are film coated, for a variety of reasons including aesthetics, taste or odour masking, enhanced mechanical strength, improved swallowability and/or protection from environmental conditions (e.g. moisture, light, air).

2. Case Study

Focus of this case study was to develop a valid methodology to shift production of metformin tablets to the largest available equipment. Tablets containing metformin and Sitagliptin (weight 1,300 mg, friability 0.8%, hardness 280 N, density 0.75 kg/L) were coated in a pilot coater (Perfima Lab 70 L Drum) to evaluate first of all optimal coating conditions for product quality and secondarily, to find out maximum spray rate/nozzle to have a starting point for subsequent scale-up.

In previous study the dependency of the coating result on the dispersion uptake of a single core was investigated. As it is difficult to apply the results of these calculations practically, the number of nozzles can be taken as a measure for this parameter. It could be shown, that by keeping the ratio of spray rate and inlet air quantity as well as the spray rate per nozzle and the drum speed constant, comparable results in different scales could be achieved. This methodology ensures similar humidity exposure to all the tablets in transit below the spray pattern: since the limiting factor is air availability and the mechanical pressure on the cores increasing the drum scale from a 70 L to a 800 L coater, we can consider this work as a step up process. Coating formulation in all the trials was the following for a +3% theoretical weight gain: Table 2 describes optimal process parameters to achieve good coating quality and process equilibrium.

Table 1: coating formulation for all the trials performed.

Table 2: optimal parameters for test 1.

In the first test spray rate per nozzle was kept at 68 g/min/nozzle and inlet air flow rate 400 m³/h/nozzle while peripheral speed was maintained at 0.67 m/sec during spray phase. Final result was optimal.
For the subsequent industrial step an evaluation of maximum spray rate/nozzle achievable was mandatory and this was found in test 2 reported in Table 3.

Table 3: coating parameters in test 2 to find max spray rate per nozzle.

Table 4: test 3 coating parameters in Perfima 200 at 100% filling.

Based on preliminary result obtained, test 3 was performed on a Perfima 200 (250 L Drum) at maximum filling percentage. The tablets bed is definitely deeper and larger in bigger equipment and this makes a linear scale-up quite complex: this is why in this paper we speak about step-up process.
Final implementation was done for further step-up of process in the direction of a even larger equipment Perfima 500 (550 L Drum) trying to maintain similar ratio of spray rate/nozzle. Given that the inlet air amount cannot be scale up linearly, the inlet air T° had to be adjusted accordingly.
Last step of this case study was to finally bring the production to a Perfima 800 (950 L Drum). On this equipment due to the large amount of tablets smoothness mixing played an important role to ensure gentle treatment of tablets during coating and also handling steps.
Parameters of Perfima 800 process are reported in Table 6.

Table 5: parameters of Perfima 500 coating process.

Table 6: coating parameters in Perfima 800.

3. Conclusions

In all trials, comparable results with regard to coating quality were achieved. This was first of all due to the geometric similarity of all equipment involved guaranteed by the Perfima design. The process was studied on a lab scale machine first and the extreme process conditions found were the base for the following scale-up. Due to the variations in the inlet air amount available at different scales causing an increase in the charge of the tablets, the max spray rate per nozzle was chosen to keep a comparable and reasonable coating time during the step-up process, as shown in Table 7.

Table 7: summary of scale up conditions.

In all the trials, a good coating surface was achieved and coating losses were kept in the range of 7-13%.
The lower coating losses were observed in the large production cycles, potentially due to better polymer uptake and distribution. Therefore, the production of coated metformin tablets is more suited to larger batches, which is appealing for the growing markets.

References

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[2] Scaling up a film coating process by keeping the ratio of spray rate and inlet air quantity constant using Kollicoat® protect as coating material and the side vented pan coater Perfima 200, “Excipient Fest Europe”, June 17-18, 2008, Cork, Ireland.
[3] Investigating the dependency of the maximum spray rate on the amount of Inlet air used, “Excipient Fest Europe”, June 17-18, 2008, Cork, Ireland.
[4] Scale-up of a pan coating process, “AAPS PharmSciTech”, 2006; 7 (4) Article 102, http://www.aapspharmscitech.org.
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