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Minitablets normally provide a more reliable in vivo dissolution performance when compared to a single unit dosage form, resulting in consistent dose-to-dose bioavailability and clinical effect.

Minitablets taste-masking into a new drum specifically designed for multiparticulate oral solid dosage form.

Introduction

Minitablets are flat or slightly curved tablets with a diameter ranging between 1.0 and 3.0 mm. They are usually filled into a capsule, occasionally compressed into larger tablets, or sometimes placed in sachets for easy administration. Used as a single or multiple-unit oral dosage forms, minitablets, thanks to smaller dimension compared to normal tablets, can pass through the stomach at a more even rate: this is very useful because drug concentration in blood can be easily reproduced. 

Minitablets normally provide a more reliable in vivo dissolution performance when compared to a single unit dosage form, resulting in consistent dose-to-dose bioavailability and clinical effect. Minitablets combine the advantages of MP dosage forms with the established manufacturing techniques of tableting and have fewer constraints compared to extrusion spheronisation. Additionally minitablets produced by direct compression are an attractive alternative to pellets since the use of liquids is avoided.
These pharmaceutical forms can be also coated and combined to achieve various releases with one formulation: diseases that require multi-target therapy approach can be treated more successfully. Film coating of minitablets brings several advantages, including: masking tastes or odors, improving swallowability, helping to positively impact patient preference, differentiating the visual appearance of product to mitigate dispensing errors, improving packaging efficiency, prevention of cross contamination, reduced tablet breakage and chipping during manufacture. Minitablets have a great potential as patient-friendly drug delivery system for targeted populations (e.g. elderly and children). In pediatric field, taste masking becomes mandatory especially if achieved by polymer that provides easy swallowing. 

 

Aim of the study

The aim of this investigation was the evaluation of coating process feasibility into an innovative pilot and production scale coater for minitablets taste-masking.

 

Methods

2.5 mm diameter placebo minitablets were produced in tableting machine Prexima 300 (IMA, Italy) by using standard feeder system equipped with flat paddles performing at 40 rpm. To achieve minitablets with good quality, 7 kN was chosen as compression force.
Placebo, supplied by Meggle (Germany), was the studied formulation containing Lactose Monohydrate, Cellulose, Aluminum Oxide and Magnesium Stearate as lubricant. Firstly, coating was performed into pilot scale Perfima Edge 30 L Drum (IMA, Italy) in order to explore feasibility of process. Secondly, once parameters were fixed process was up-scaled in Perfima Edge 200 L Drum (IMA, Italy).
In order to taste-mask the minitablets, coating formulation provided a combination of Surelease and Opadry, kindly supplied by Colorcon (UK). 

 

Formulation

Formulation Coating formulations providing Surelease and HPMC based Opadry, as pore-former, with ratio of 80:20 were prepared by dispersing the Opadry in deionized water and then adding to Surelease to a total solid content of 12% w/w.
Insoluble in water, Ethyl cellulose contained in the Surelease acts as the taste-masking agent by delaying the release of the drug in the mouth, while Opadry is used as a pore-former in the coating, which allows immediate release of the drug once in the stomach. Due to high tablets total surface a 10% weight gain was required as process target. Ratio between Surelease and Opadry was kindly suggested by the supplier (Colorcon, UK) Ethyl cellulose contained is a non ionic polymer providing very low potential for drug interactions.

 

Parameter m.u. Pilot Production
Pan load kg 23 82.50
    10
Theoretical weight gain kg 12
Solids concentration kg    
Opadry 03K19229 kg 0.46 1.65
Surelease E-7-19020 kg 7.36 2.64
Water kg 11.347 40.7
Total quantity to be applied kg 19.167 67.75

Table 1: coating formulation for both pilot and production scale batches.

 

Parameter m.u. Perfima Edge 30 L Perfima Edge 200 L
Batch size kg 23 82.50
Pan speed rpm 10-12 8-9
Periphal speed m/s 0.45-0.54 0.50-0.57
Inlet air q.ty m3/h 700 2600
Inlet air T° °C 56/68 60/70
Cores T° °C 42/45 42/45
Negative pressure Pa -30 -30
Spray rate g/min 120 400
Atomisation pressure bar 1.5 1.8
Pattern pressure bar 1.4 1.6
Gun distance cm 20 22
Guns type and number ABC Schlick – 1 ABC Schlick – 4
Nozzle diameter mm 1.2 1.2
Process time min 160 170

Table 2: coating process parameters for both pilot and production coaters.

 

Results and discussion

Tableting process allowed a smooth and stable performance that resulted into minitablets with good quality and ideal technological characteristics for the following coating step: weight 13 mg, hardness 30 N and friability <0.1%. 

In order to achieve this result, the feeding system had to be properly chosen: different paddle shape were tested to get the best Relative Standard Deviation on weight. Standard paddles were found as the better configuration for this kind of product achieving stability over the time. Once the feeding was defined, punch position inside the dies was accurately chosen in order to maintain tablet strength in all the minitablets produced. Thanks to parameters optimization, process was pushed at its best with the highest turret speed possible: 90 rpm was the best point to get process solidity.
Perfima Edge, IMA vented pan coater equipped with wedge wire screen drum, was used in this study. This pan coater is specifically designed for coating of small substrates such as pellets and it maintains the same drum shape, geometry and spray system of the standard pan for tablet coating, while small wedge wires are fitted into the drum to allow the passage of air during the process. Specially designed mixing baffles were welded to the center and the sidewalls of the drum, in order to handle all types of substrates with different shapes and sizes.
As first step, preliminary coating tests were performed in pilot scale to investigate coating formulation and find the right parameters for a 20 kg batch. Pilot trials were conducted in triplicate to confirm process repeatability before scaling up.
The scale up from lab to production scale was easily performed thanks to the maintained geometric similarity among the equipment used. Process parameters were harmonized in order to maintain the tablets temperature stable around 42-45°C, and process time was always below 3 hours as a result of a 10% weight increase.
Final yield of all trials were in the region of 99% due to process parameters optimization. Coating parameters are described in table 2 for both equipments.
The coated minitablets exhibited good appearance with no visual defects or roughness.

 

Conclusions

Due to the smooth surface of pan internal surface no abrasion or damage of minitablets were observed. The new drum design providing slots instead of perforations, demonstrated to be a good technology to coat minitablets for taste masking purposes.
The wedge wire drum presented some benefits when compared to the same process performed  in solid pan or fluid bed, indeed batch sizes can be coated in smaller sized equipment. Compared to solid wall coating pan, side vented pan coating equipped with wedge wire screen drum allowed high inlet air quantities resulting in higher spray rates and economical short process times; similar to conventional perforated drum coaters. While compared to the fluid bed processor, this technology provides two main advantages: firstly, it comes with a much smaller footprint, and secondly, the spray guns are accessible during the process. Additionally, drum coating processes can easily be controlled thus simplifying up-scaling procedures.

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