End -point determination in wet granulation
Most challenging task while performing wet granulation in high-shear mixers, is the detection of end point and reproducibility of same end point by controlling various process variables. End-point can be defined by the formulator as a target particle size mean or distribution. It has been shown that once you have reached the desired end-point, the granule properties and the subsequent tablet properties are very similar regardless of the granulation processing factors, such as impeller or chopper speed or binder addition rate. This is called “the principle of equifinality”. The ultimate goal of any measurement in a granulation process is to estimate viscosity and density of the granules, and, perhaps, to obtain an indication of the particle size mean and distribution. These factors may be monitored and controlled by use of suitable measuring devices to achieve reproducibility in the process. Various primary independent factors in different granulation processes which can affect the granulation end point are presented in (Table 1).
TABLE 1 Factors affecting high-shear wet granulation process
|· Impeller Speed
· Chopper Speed
· Liquid Flow rate
· Impeller Load
· Liquid addition
· Mixing time
|· Amount of liquid binder
· Type of binder
· Surface tension
· Particle size distribution
|· Size and shape of mixing chamber
· Size and shape of impeller
· Size and shape of chopper
While performing wet granulation in a high-shear mixer, formulation scientist is in regular concern with few variables which plays leading role in determining the end product properties, brief description of these variables are given below:
Measurements of Power Consumption of the mixer motor have been widely used for end point determination because measurement is economical and well co-related with the growth of granules . Power consumption can also be co-related with mean particle size of the granules although it is not linear in the entire range . Intra granular porosity also shows some co-relation with power consumption . Pharmaceutical high-shear mixers are generally equipped with one or more device for such measurements. Significant drawback of the power consumption measurement is that it reflects load on the motor rather than load on the impeller where actual action is being performed and can vary with time regardless of the load. Lindberg  co-relate the power consumption and the saturation level S of the granules as shown in eq.-1 below.
S = H (1– ε) / ε * P (eq-1)
The saturation level S of an agglomerate is defined as the ratio of pore volume occupied by liquid to the total volume of pores available in the agglomerate. Where H is the mass ratio of liquid to solid, ε is the intra-granular porosity and P is the density of the particle relative to the density of the liquid
Load on the main impeller can be estimated by measuring current in DC motor because torque generated by the impeller is proportional to the current applied. Current meter (ammeter can be used for small scale DC motors. In case of AC motor impeller load does not vary linearly with the current applied therefore current is completely in-effective as a measurement of impeller load in AC motor
Power ~ Torque * Speed
Impeller power consumption can be calculated as a product of the direct torque, rotational impeller speed, and a coefficient (usually equal to 2Πtimes a unit conversion factor, if required). Impeller torque, on the other hand, is directly related to the load on the impeller. It was observed that when the end-point region of a granulation is reached, the frequency distribution of a power consumption signal reaches a steady state .
In wet granulation process change in impeller torque and power consumption of the impeller occurs as a result of change in the cohesive force or the tensile strength of the granules in the powder bed. Therefore impeller torque is an excellent in-line measurement of the load on the main impeller. Torque rheometer has been extensively used for the off- line measurement of torque required to rotate the blade of the device and this torque has been used to access rheological properties of the granules and the end point of the granulation process. The torque value thus obtained was termed as “measurement of wet mass consistency” which describes the rheological properties of the wet mass.
Liquid/ Binder solution Addition
Both moisture content and rate of addition of binding solvent is important in successful attainment of granulation end point. Mean granule size is strongly dependent on the specific surface area of the excipients, as well as the moisture content and liquid saturation of the agglomerate. During the wet massing stage, granules may increase in size to a certain degree while the intragranular porosity goes down. Binder addition rate controls granule density, while impeller and chopper speed control granule size and granulation rate. There are conflicting reports on preferred method addition to the granulating mixture. Some recommend not to add dry binder to the blend because homogeneous binder distribution cannot be assured, other recommend dry binder addition. However, slow addition of solvent or binder solution to the blend is a preferred method of choice to avoid local over wetting.
An increase in wet-mixing time resulted in a decrease in intragranular porosity, as measured with mercury intrusion, an increase in mean granular size, and an increase in bulk density. The strength of granules was also inversely related to the intragranular porosity.
Impeller or Motor Shaft Speed
Rate of impeller rotation could be used as some indication of the work being done on the material. Since the motor or impeller power consumption is proportional to the product of torque and speed, the latter is an important factor in evaluating the corresponding load. Other factors that may affect the granules quality includes spray position, spray nozzle type and the product composition. Variables such as mixing time and bowl or product temperature are not independent factors in the process but rather are responses of the primary factors listed above. Various articles have been published regarding end point detection in high shear wet granulation using sound and vibration signals and using Infra-red (IR) sensors. Emerging technologies for the detection of end point in wet granulation process are –
- Acoustic Emission Sensors Technology
- Near Infra-Red (NIR)
- Focused Beam Reflectance Measurement (FBRM)
End Point in a wet granulation process is characterized by rheological properties of the wet mass such as density, viscosity etc which are in turn a function of particle size, shape and other physical properties. End Point can be quantified with the help of dimensionless numbers such as Newton Power Number (Np), Froud Number (Fr), and Reynolds Number (Re) that will assume a certain numeric value for every state (condition) of granulate. For eg under fixed processing conditions Np will be proportional to the Net Power Consumption ∆P for any end point. Thus, in order to reproduce an end-point, it is sometimes sufficient to monitor power of the impeller (or the motor) and stop when a predefined net level of the signal is reached.
Np = ∆P / (ƥ n d) (Power Number)
Fr = n d / g (Froude Number)
Re = d n ƥ / ἡ (Reynolds Number)
P = Power required by the impeller or motor
ƥ = Specific density of particles (kg / m3)
n = Impeller speed (revolutions / s)
d = Impeller (blade) diameter or radius (m)]
g = Gravitational constant (m / s2)
ἡ = Dynamic viscosity
Newton (power) number Np, which relates the drag force acting on a unit area of the impeller and the inertial stress, represents a measure of power requirement to overcome friction in fluid flow in a stirred reactor. In mixer-granulation applications, this number can be calculated from the power consumption of the impeller or estimated from the power consumption of the motor. Froude Number has been described for powder blending and was suggested as a criterion for dynamic similarity and a scale-up parameter in wet granulation. The mechanics of the phenomenon was described as interplay of the centrifugal force (pushing the particles against the mixer wall) and the centripetal force produced by the wall, creating a “compaction zone”. Reynolds numbers relate the inertial force to the viscous force. They are frequently used to describe mixing processes and viscous flow, especially in chemical engineering