The science and physics of how liquids flow and solids are deformed form the basis of what is known as rheology. Here, we explain what makes a fluid either “newtonian” or “non-newtonian” while the use and importance of rheology in the pharmaceutical industry are explored.
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Panta Rhei: Everything Flows
In the most basic of terms, rheology can be considered the study of flow behavior in materials, whether solid, liquid, or gas. Rheology recognizes that certain solids respond with plastic flow in response to an applied force. These solids can be considered fluids, or more specifically, to experts in the field, “non-newtonian fluids”, but what is such a material?
Fluids flow at different speeds, making their viscosity one of their most important properties. Viscosity is the amount of internal friction within a fluid that determines its consistency or “stickiness”.
Although more famous perhaps for discovering gravity, Newton derived the concept of viscosity and, hence, we have “newtonian fluids” and “non-newtonian fluids”. The former constitutes only a small group but does count water and air among examples.
Newtonian fluids have constant viscosity, where it is independent of flow speed or “shear rate”. This is the rate that fluid layers “shear” or move between each other when stress or a force is applied (in a sense, when working the material). In other words, there is no viscosity coefficient associated with the flow connected to these types of materials.
Rheology describes and assesses the non-newtonian materials. It covers the intersection between the field of plasticity (or elasticity) and fluid dynamics and, in practical terms, the study of how the architecture of material and its molecular size (whether working at the micro or nanoscale, for example) influences mechanical behavior. It can be exploited to examine the evolution of this behavior from discrete particles to bulk material or mass. At the same time, it can also assess the associated diverse flow properties exhibited resulting from manipulation. In addition, rheology also explores a materials’ internal structure and the particle size distribution in solid suspensions.
Within the pharmaceutical field, substances with complex microstructures and materials that inherently exhibit complex flow behavior are the norm. With a need to have a myriad of “routes of administration”, the industry is driven by the supply of a bewildering array of consumables to match this need. Frequently, a knowledge of the mechanical behavior of these consumables can only be derived from applying rheology.
Determining how a pharmaceutical should be administered can be dependent on how efficiently the recipient’s therapeutic target(s) needs to be reached. For example, in insulin, metabolization in the gastrointestinal tract can occur before reaching the bloodstream, which is not desirable and therefore dictates intravenous delivery.
Vomiting may make it difficult to administer medication orally, necessitating alternative routes of administration. Among these sublingual, buccal, nasal, suppository, and inhalational are all possibilities, placing great importance on particle size and material form within which medication is held.
The broad marketing term explaining how to use a pharma product is known as the “dosage form”. Depending on the route of administration (again, different medical conditions warranting different routes), there is a requirement for dosage forms to be manufactured in different shapes and physical states.
Between herbal and non-herbal forms, the product-configuration list is extremely extensive taking in, as it does, pills, tablets, capsules, syrups, patches, gels, lotions, ointments, creams, emulsions, and pastes together with parenteral suspensions (these are materials that get applied or occur on body parts other than the alimentary canal or the mouth).
Various dosage forms may exist for the same pharmaceutical, while dosage might refer to the apportion of constituent substances contained in the formulation; sometimes, a very particular ingredient mix of active and inactive components (excipients) makes up the content. With such a comprehensive mix of configurations and dosage forms, the reliance on and importance of rheology in optimizing the processing and performance of pharmaceuticals emerges to those previously unaware.
Drug Formulation and Process Development
Rheological characterization tools, such as viscometers, allow drug producers to directly affect how a drug is formulated and developed, cutting across parameters and conditions to arrive at product characteristics that can be quantified. This capability helps determine drug efficacy, the quality of the raw components, and ultimately the quality of the finished product. These are fundamentals in the overall healthcare cost of a prescription amongst other valuable information that rheological techniques can yield in making a product effective.
Viscosity measurements can be taken by applying stress and inducing flow, bench-marking the viscosity as a function of shear stress. This can play a crucial role in evaluating the characteristics of a molecule which, in turn, can make reformulations using alternative ingredients a serious proposition where appropriate. For example, non-sterile liquid formulations (such as soft-gel capsules and suspensions) are derived from a diverse range of compounds. Scalability is often only possible because of readily available excipients with known properties and sufficient physical stability.
Critical in Pharmaceutical Processing: Quality Control
Quality control is a prerequisite when it comes to pharmaceuticals. To make it to market, the purity of a particular product and its identity must be verified. Typically, benchmarking is done against pre-defined standards using rheology methodology. Reproducibility is also key, and ensuring consistency from one batch to another at every stage of a manufacturing process is essential, particularly in drug production.
Important flow properties can be ascertained, maintaining the superiority of the product. In other cases, rheology is deployed where the solubility of pharmaceuticals needs to be critically assessed often in determining the suitable vehicles or transport mechanism.
Non-Drug Rheology Pharmaceutical Testing
Beyond drug preparation, rheology gets applied in stress and strain measurements, for example, in products where creep and recovery might be essential properties in a material being used to restore tissue or muscle damage. It extends into testing everything from measuring eye drop surface tension to dry powder inhalers to dermatological products where sensory characteristics or spreadability might be a priority.
Providing the insight necessary to predict an emulsion’s stability or determine an anointment’s resistance to being washed-off are other aspects of the pharma sector where rheology can be effective. The success of a new ophthalmic product (such as eye drops) may depend on an understanding of how to to make it easy to pour from a bottle or a tube. It might be the case that a product’s ability to lubricate, be retained, or hold film-forming characteristics will provide its unique selling point.
Whatever material properties the developer requires, they most likely evolved from data garnered from rheology.
References and Further Reading
Aho, J., et al. (2016) Rheology in Pharmaceutical Sciences. Analytical Techniques in the Pharmaceutical Science. https://doi.org/10.1007/978-1-4939-4029-5_23