Feasibility Studies Regarding Manufacturing of Submicron Systems Using a New „Rotor/Rotor“-Processing Facility
Keywords: submicron emulsions, submicron suspensions, process parameters, design of experiments
Introduction
Processing facilities with homogenizer basing on the „rotor/stator“-principle are utilized in different industries in the manufacture of liquid emulsions, liquid suspensions and semi-solid dosage forms (1).
In common used processing plants the homogenization process of these preparations can be mainly influenced by varying the speed of the rotor with respect to the fixed stator, or by concrete design of rotor and stator. In general the shearing effect and the transportation effect of the homogenizer are greater at high rotation speed than at lower.
However, the maximum shear rate is limited by the dimensions of the “rotor/stator”-system and the maximum rotation speed of the drive motor.
Furthermore it can be stated, that the shearing and the transporting effect are directly interlinked. Therefore it might be possible, that with a too high homogenizer or motor speed the shearing effect becomes so great, that the substance respectively formulation to be homogenized is affected negatively and could even be damaged.
In this study a “rotor/rotor”-apparatus with a special designed homogenizer, the so-called “Co-twister system”, has been used (2). It is installed under the vessel and powered by two water-cooled, frequency-controlled drive motors which can be adjusted independently from each other.
- Fig. 1
A “rotor/rotor”-system results, which leads to new possibilities in the homogenisation process (Fig. 1).
By means of a dynamic stator, which can be driven separately and independently of the rotor, the homogenizing and transporting can be influenced in a great variety of ways and can be adopted to the particular production needs. The dynamic stator can be driven in the same direction or contrary to the rotor, so that the shearing effect can be varied continuously within great ranges.
The shearing effect approaches “zero” if the dynamic stator and the rotor rotate with identical or similar speed in one direction.
On the opposite it reaches its “maximum” at the maximum contrary speed of rotation, while the same shearing effect requires a significantly lower absolute speed of rotation when compared to other homogenizers. In contrast to conventional “rotor/stator”-systems the “rotor/rotor”-technology offers the possibility to break-off the fixed combination between shear rate and flow rate. It is possible to reach either at constant revolutions of the rotor a higher shear rate by changing the rotation direction of the dynamic stator, or to adjust at a constant shear rate different flow rates at various “rotor/rotor”-revolutions. As a result a break off of shear rate and flow rate is reachable. In addition the maximum shear rate of this “Co-twister system” is possibly much higher compared to conventional processing plants.
Investigation scheme
Low viscous, liquid dispersions like emulsions or aqueous lipid dispersions with droplet sizes smaller than 1µm, also called “submicron systems”, have gained special interest as drug delivery systems in cosmetics and pharmaceuticals (3,4). A series of experiments have been performed to answer the question if the described “rotor/rotor”-system is of advantage in the production of those “nanosized”-formulations.
First a general manufacturing process for such submicron systems was established. Subsequently this manufacturing process was varied during the various series of experiments. At different temperatures prototype formulations were homogenized with different shear rates for a certain period of time. During and at the end of the production process the particle size distribution of the product was controlled via laser diffraction measurements.
Critical process parameters
First the reproducibility of the manufacturing process as a whole was studied. As criterion the d50 value of the resulting particle size distribution was defined. Studies followed, in which at a constant shear rate – but at different revolutions of the “rotor/rotor”-system – the manufacturing procedure was performed to check the break-off between shearing and pumping in this special type of processing facility.
The possibly critical process parameters were investigated using a 23-factorial design, which represents a rational method to study production processes. The effects of the tested parameters were calculated and the results – d50 values – were statistically evaluated according Yates for significance (5). The parameters “rotation speed during homogenisation” (57 m/s or 22 m/s), the “rotation speed during cooing” (57 m/s or 22 m/s) and the “temperature during homogenisation” (80°C or 20°C) were investigated at two levels.
Comparative studies
The aim of these experiments was to investigate if “rotor/rotor”-technology allows to imitate common used “rotor/stator” processing devices, although having a different construction respective design of rotor and stator. Therefore liquid/liquid or solid/liquid dispersions were prepared at different shear rates and the resulting particle size distributions were determined and compared. A second goal of these studies was, depending on the different model formulations, to clarify which droplet size in minimum is achievable.
- Table 1
Prototype formulations (Table 1)
As prototype formulations for highly dispersed emulsions the common known formulations “L1 and L2” - basing on lecithin – were chosen. They are able to be produced with a droplet size smaller 1µm by high pressure homogenisation (6).
The formulations “I, II” for the intended lipid particles in the nanometer scale were deduced from literature (7).
Manufacturing process (Fig. 2 and 3)
Equipment
Rotor/rotor-homogenizer:
Symex, type CML 30, Co-Twister,
Ser.-Nr.: SY900558 (2001)
Rotor/stator-homogenizer:
Becomix, type RW 15,
Ser.-Nr.: 011/1-20 (1986)
Laser Particle Sizer:
Symatec, type SUCELL
Ser.-Nr.: 674 (1999)
- Fig. 2 + Fig. 3 + Fig. 4
- Table 2 + Fig. 5
Results
Critical process parameters
Concerning the reproducibility of the production process 3 batches each of the formulation “L1” were produced at a low (9000 rpm, 10 m/s) and a high shear rate (9000 rpm, 57 m/s). In dependency of the processing time samples were taken with the aid of a peristaltic pump and a tube which was directly brought into the vessel.
It can be seen from Fig. 4, that the reproducibility of the manufacturing process concerning the particle size distribution is impressing. The standard deviation of the d50 values are at lowest and highest shear rates only about 2%.
A series of experiements with formulation “L1” at a constant shear rate (22 m/s) – but at different revolutions (3000rpm to 9000 rpm) of the “rotor/rotor”-system – showed, that there is no dependency between the particle size distribution and the revolutions of the stator at a constant shear rate. It is obvious, that although the number of revolutions and the rotation direction changes an influence on the particle size is not given. This is the proof for the break-off between flow rate and shear rate in this unique processing device (Fig. 5).
It is well known, that the particle size distribution of emulsion systems is influenced by various parameters during production, mainly the temperature and the shearing forces during homogenization and cooling (8).
In order to judge which of the possibly influencing factor are decisive, an investigation according 23 factorial design was performed with prototype formulation “L1” (Table 2).
Evidance was given, that under these conditions the influencing factor “shear rate during homogenization and cooling” has a statistical influence on the target dimension “particle size distribution”. By this reason the following comparative experiments were performed only with different rotations speeds as investigative parameter, while all other process settings were kept constant.
Comparative studies
It was found in the series of experiments with the intension to produce “submicron emulsions”, that the homogenizer speed has a high impact on the product quality. Fig. 6 shows the particle size depending on the different shear rates. They are accomplished by different revolutions and rotation directions of the dynamic stator. Right from the interrupted yellow line rotor and dynamic stator are working in different rotation directions. This shear rates can not be realized with a conventional “rotor/stator”-apparatus. A strong dependency of the particle size on the shear rate and the formulation could be seen. The minimum droplet size for the L2 formulations is reached at a rotation speed of about 40 m/s in contrast to the L1 formulations containing 10% lipids where the optimum shear rate is about 57 m/s. For the indented “submicron suspensions” nearly identical results were found. Once more a clear dependency of the d50 values on the shear rate and the formulation was given. In certain cases lipid particles smaller 1 µm can be observed (Fig. 7).
Comparative studies using the “rotor/stator”-apparatus were restricted through its design of rotor and stator to 22 m/s in maximum (Fig. 8 and Fig. 9).
The processing devices are different concerning their homogenization efficacy. d50 values for formulations produced in the “rotor/rotor”-system are even at lowest rotating speed comparable to the in minimum reachable d50 values with the conventional apparatus.
On the other hand identical particles sizes are available at certain “pump rate”/”shear rate”-ratios.
- Fig. 6
- Fig. 7 + Fig. 8 + Fig. 9
Conclusions
An unique processing facility was investigated intensively. During various experiments it was found, that the two independent drive motors for the rotor and the “dynamic stator” can be precise controlled and adjusted. As a result this innovative “rotor/rotor”-system allows extreme reliable production processes in terms of precision and variety. An explanation for the differences in particle size at identical rotor speed is possibly the different constructions of the used rotor/stator-unit which leads to a different homogenization efficacy. Evidence was also given, that “rotor/rotor”-systems are able to replace conventional “rotor/stator”-systems.
“Rotor/rotor”-homogenizer are able to produce particles smaller than 1 µm and thus give comparable results to high pressure homogenization.