What are the differences between rolling ball viscometers and rotational rheology for calculating parenteral product viscosity?
What is viscosity?
Viscosity is the amount of internal friction (or internal resistance) between components in a fluid. Honey is an everyday example of a highly viscous product. Products with high viscosity are considered “thick” and flow slowly. In contrast, water is an example of a fluid with low viscosity. Products with low viscosity are considered “thin” and flow quickly and easily. A fluid’s flow speed depends on how fast the molecules in a fluid can rearrange and move past each other. Thus, liquids with small molecules tend to have low viscosity. Liquids with long-chain molecules (such as hyaluronic acid) have higher viscosity. Also, liquids with molecules that can form bonds with each other are more viscous. The bonding of glucose and fructose in honey is why honey is so viscous.
What types of injectable products are viscous?
Viscous injectable formulations often have high concentrations of large molecules or non-aqueous solvents. Highly viscous formulations contain both. Examples of large molecules include monoclonal antibodies, proteoglycans, and high molecular weight polymers. Proteoglycans like hyaluronic acid are included in many cosmetic or parenteral products. Additionally, controlled release versions of parenteral formulations often include high molecular weight polymers. When it comes to non-aqueous solvents, oil-based product formulations tend to be the most viscous.
How is parenteral product viscosity calculated?
The United States Pharmacopeia offers three methods for viscosity determination. The first method is the viscosity-capillary viscometer approach (USP 911), which is the focus of this article. The second method is a rotational rheometer technique (USP 912). The rolling ball viscometer method (USP 913) is the third option for calculating viscosity.
What types of fluids do rolling ball viscometers and rotational rheometers assess?
Rolling ball viscometers are used to determine the viscosity of Newtonian fluids only. In contrast, rotational rheometer methods can determine the viscosity for Newtonian fluids and apparent viscosity for non-Newtonian fluids. As viscosity depends on temperature, the temperature of the samples measured for either capillary viscometer or rotational rheology techniques should be controlled to within ±0.1°C when evaluated.
What methods are used for rolling ball viscometer vs. rotational rheometer calculations?
Rolling ball viscometer calculations are performed using rolling ball viscometers. Viscosity can be obtained from rotational rheometers through not one but four different devices: spindle viscometers, concentric cylinder rheometers, cone-and-plate rheometers, and parallel plate rheometers.
What are the differences between rolling ball viscometers and rotational rheology for viscosity calculations?
All rotational rheology methods measure the force (torque) acting on a rotor when it rotates at a constant angular velocity (or rotational speed) in a liquid to determine viscosity. In contrast, rolling ball viscosity measurement is based on Stokes’s Law, where the tube of the rolling ball viscometer is considered a capillary. With Stoke’s Law, measuring a ball’s rolling time within an inclined cylindrical tube filled with the fluid under assessment can determine a liquid’s viscosity. The ball’s velocity is determined by measuring the time the ball takes to travel a fixed distance (i.e., the distance between two ring marks or measuring sensors). For each measured velocity (rolling time), the resulting viscosity can be expressed as dynamic viscosity (mPa x s) and kinematic viscosity (mm2/s) for a sample of known density.
Spindle viscometers are the least precise of the four rotational rheology methods. Indeed, spindle viscometers cannot calculate an absolute fluid viscosity if there is a large gap between the spindle and the container wall. In cases with large gaps between the spindle and the container wall, the torque to maintain a given angular velocity for the spindle viscometer measures the liquid resistance to flow (apparent viscosity) only.
In terms of cost, rolling ball viscometers are about $3,500 for a basic benchtop model. Rotational rheometers fall under two categories: spindle torque rheometers and dynamic rotational rheometers (concentric cylinder, parallel plate, and cone-and-plate rheometers). Spindle rheometers that determine approximate viscosity based on torque are the cheapest and cost between $2,000-$5,000. Other dynamic rotational rheometers range from $35,000 at the low end and $150,000 at the high end.
Rolling ball systems are simple to use and involve filling the rolling ball viscometer tube with a sample and allowing the device to measure the time required for the ball to roll a fixed distance. The tube and ball combination is chosen based on the anticipate viscosity range of the fluid sample. Additionally, the tube’s inclination angle is selected based on an anticipated ball rolling time of at least twenty seconds. Rotational rheology systems are also simple to use. Differences between the various rotational rheology systems are detailed below.
What are the differences between spindle viscometer, concentric cylinder rheometers, cone-and-plate rheometers, and parallel-plate rheometers?
Spindle Viscometer
For a spindle viscometer, the apparent viscosity is determined by rotating a cylinder-shaped or disk-shaped spindle in a large volume of liquid. An example of a spindle viscometer is shown in Figure 3.
Concentric Cylinder Rheometers
For a concentric cylinder rheometer, the apparent viscosity is measured by placing the liquid sample in a gap between the inner cylinder and the outer cylinder of the rheometer. In these rheometers, either the outer cylinder (the cup) or the inner cylinder (the bob) rotates. Rotating-cup rheometers are known as Couette systems, while rotating-bob rheometers are called Searle systems. Controlled-stress and controlled-rate concentric cylinder rheometers are available with absolute geometries (e.g., tiny annular gaps between concentric cylinders). Absolute geometries allow the apparent viscosities for non-Newtonian fluids to be calculated. Controlled shear stress rheometers measure the shear rates from applying a given force or torque (stress). Whereas controlled shear rate rheometers measure the shear stress (the torque on the rotor axis) resulting from a given shear rate (rotational speed). An example of a concentric cylinder viscometer is shown in Figure 4.
Cone-and-Plate Rheometers
For a cone-and-plate rheometer, the sample liquid is placed into a fixed gap between a flat disk (or plate) and a cone forming a defined angle (ß). The cone’s angle keeps a constant shear rate due to the increase in both the gap between the cone and the plate as the distance increases from the origin. Viscosity measurements can be performed by either rotating the cone or rotating the plate. As the sample volume for cone-and-plate rheometers is small, even a tiny loss of the solvents can cause a significant change in the measured viscosity. Thus, precautions must be taken when measuring sample viscosities, especially for samples with volatile solvents. An example of a cone-and-plate viscometer is shown in Figure 5.
Parallel Plate (Parallel Disk) Rheometers
Parallel plate rheometers are similar to cone-and-plate rheometers. The difference between parallel plate rheometers is that the sample to be measured is introduced into the gap between a flat plate or disk and another parallel flat plate or disk. Generally, measurements with a parallel plate rheometer are made by keeping the lower plate or disk stationary as the upper plate or disk is rotated at a constant angular velocity, ω. Different from the cone-and-plate rheometer, the shear rate between parallel plates increases as you move away from the origin of the axis of rotation. Shear rate increases away from the origin of the axis of rotation because of the increasing speeds for angular velocity with a constant gap. Advantages of the parallel plate rheometer include ease of sample loading for very viscous liquids and its suitability for determining the viscosity of particulate suspensions. If a suspension is assessed, the gap should be set high enough to avoid grinding particles between the parallel plates. In the absence of large particles, the parallel plates may be used at narrower gaps. Like cone-and-plate rheometers, the evaporative loss of a solvent can significantly affect the sample’s measured viscosity. Thus, precautions need to be taken to minimize solvent loss. An example of a parallel plate viscometer is shown in Figure 6.
Summary
Overall, viscous injectable formulations often have high concentrations of large molecules or non-aqueous solvents. With large protein biologics popularizing the drug therapy market, viscosity calculations for viscous products are essential for determining delivery mechanisms and accurately filling parenteral products. Rolling ball viscometers and rotational rheology are two of three USP-approved ways to calculate viscosity. Unlike rolling ball viscometry, which only calculates viscosity for Newtonian fluids, rotational rheology can calculate viscosity for Newtonian fluids and apparent viscosity for non-Newtonian fluids. Rolling ball viscometers uses one type of device, a rolling ball viscometer. On the other hand, rotational rheology methods use four distinct devices: spindle viscometers, concentric cylinder rheometers, cone-and-plate rheometers, and parallel plate rheometers. Spindle viscometers are significantly less expensive and the least accurate of all the rotational rheometer devices. Rotational rheology devices are more expensive than rolling ball viscometers. Parallel plate rheometers are particularly good at evaluating fluid suspensions. However, rotational rheology methods must be cautiously performed if assessing volatile liquids. Thus, for non-Newtonian fluids or suspensions, it is recommended to use a rotational rheology method. For volatile, Newtonian fluids, use a rolling ball viscometer. All in all, when filling a viscous parenteral or cosmetic product, ensure you choose a contract manufacturing organization to support your sterile filling needs.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling. MycoScience also offers Preservative Efficacy Testing, Sterilization Validations, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, Bacterial Endotoxin Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
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