1. Rheology of Biological Systems
Ref. Book: Applied Physical Pharmacy. Ed. Mansour M. Amiji, Beverly J. Sandmann, McGRAW-Hill, 2003
Rheological properties of blood
Blood rheology has been used in diagnosing and treating different types of diseases. Blood from a normal person exhibit a fairly unique rheological profile in that it is non-Newtonian at lower shear rates and become Newtonian beyond the shear of 100/sec. At lower share rate the viscosity is higher as a result of aggregates of the erythrocytes. Above the shear rate of 100/sec, the viscosity of blood remains constant (about 3.0 cps).
The rheologic profile of blood affected drastically by disease states in which the concentration of cells and protein changes. Fore example in the case of polycythemia, the viscosity of blood increases sharply while the oppsite is observed in patients of lower erythrocyte counts such as patients with anemia. In certain congenital disease where the patients suffers from both polycythemia and high fibrinogen concentration in the blood, the peripheral circulation is completely impaired and their blood has the consistency of a paste.

2. Rheological properties of Mucus
Mucus is a gel–like material secreted by the epithelial cells on the mucosal surfaces of the respiratory tract, gastrointestinal tract, genitourinary tract and the eye. Primarily, mucus serves a protective function guarding the underlying mucosal tissue against digestive enzymes and preventing infectious organisms from coming in contact with the host at the first site exposure. Mucus also has other functions such as lubrication (the eyes).
The mucus gel is a heterogeneous mixture of mucus glycoproteins (that are made up of subunits that are covalently bonded through disulfide linkages), phospholipids, enzymes and water.
The normal function of the mucus is very much dependent on the rheologic properties that changes from gel-like to fluid consistency upon increase in the shear rate.
In the respiratory tract, one of the complications of the cystic fibrosis, a congenital disease, is abnormality in the secretion and consistency of the bronchial mucus leading to childhood disorders of the respiratory tract. Due to the decreased ionic content and water, the mucus becomes extremely viscous, leading to obstruction of the airflow into the lungs which might cause upper respiratory infections and other complications. Mucolytic drugs should be taken to break the disulfide bond of the mucus allowing the patient to expel the mucus.
In the G.I.T, it has been suggested that helicobacter pylori secreted an substance that decreases the viscosity of the stomach mucus allowing the enzymes and acid to diffuse into the tissue resulting in ulcer formation.

3. Rheological properties of Synovial fluids
Synovial fluid is viscous (egg-white consistency) liquid present in all the skeletal joints of the body. It is composed mainly of hyaluronic acid, proteins such as albumin and water. The volume of the synovial fluid is about ml even in large joints such as the knee. Hyluronic acid is a mucopolyssacharide that forms highly viscous aqueous solution.
The function of the synovial fluid is to protect the skeletal joints through lubrication and provide a medium that acts as a shock absorber.
In inflammatory conditions such as rheumatoid arthritis, the molecular weight and concentration of hyaluronic acid decreases sharply leading to a decrease in the consistency of the synovial fluid. To restore the joint function, intraarticular injection of hyaluronic acid has been found to be effective.

4. Rheologic properties of biological fluids substitute
Example: tear substitute in dry eye syndrome
High molecular weight (MW) polymers with water binding properties and high viscosity have increasingly been used as hydrogels for ophthalmic applications. Their use has three advantages.
Firstly, in artificial tears, they soothe, protect and lubricate the ocular surface, thus relieving the symptoms of dry eye syndrome.
Secondly, in solutions for contact lens wearers, they also provide better and prolonged comfort to contact lens wearers through moisturizing, lubrication, and reduction of the blink frequency.
Thirdly, in viscous eye drops loaded with a drug, they increase the contact time with the ocular surface, and thereby improve the bioavailability of drugs.
Bioadhesive properties of some polymers contribute also to the improvement of the bioavailability.
The main polymeric materials that serve the aforementioned functions include cellulose derivatives (e.g., hypromellose, carmellose, hydroxyethyl cellulose), poly(vinyl alcohol) (PVA), carbomer, poly(vinyl pyrrolidone), polyethylene glycol, and dextran.
These lubricating and rewetting agents are generally well tolerated at the concentration level found in commercial eye drops. However, some of the most viscous formulations are uncomfortable and lead to blurred vision, stickiness, and formation of a crusty residue.
In addition, some of these polymers are Newtonian and do not shear thin by eye blinking, which limits their spreadability on the ocular surface and thus their efficacy.

5. To ease discomfort and overcome these limitations, growing attention has thus been paid to non-Newtonian and particularly to pseudoplastic polymers such as hyaluronic acid (HA)
HA is a high molecular weight, natural and linear polysaccharide. This biocompatible, nonimmunogenic and biodegradable polymer is one of the most hygroscopic molecules in nature and hydrated hyaluronic acid can contain up to 1000-fold more water than its own weight.
These exceptional water retention properties result in enhanced hydration of the corneal surface. Moreover, applications of ophthalmic formulations containing hyaluronic acid reduce tear elimination and enhance precorneal tear film stability, which is a useful property against dry eye syndrome.
Its non-Newtonian and shear thinning properties grant HA solutions with a high viscosity at low shear rate (when the eye is open) and a low viscosity at high shear rate (during blinking) thus allowing an even distribution of the solution, improving lubrication of the ocular surface, retarding drainage, improving bioavailability, and reducing discomfort.
Another important feature of this high molecular weight and anionic biopolymer is its muco-adhesivity, which provides effective coating and long-lasting protection of the cornea as well as extended residence times on the ocular surface.
Finally, when topically instilled on the eye, hyaluronic acid has been shown to promote physiological wound healing by stimulating corneal epithelial migration and proliferation of keratocytes and to reduce the healing time of corneal epithelium.

6. Topical ophthalmic solutions should exhibit a certain degree of viscosity to prevent immediate drainage from the ocular surface and to provide there high efficacy and long residence time.
However, the solutions should not be too viscous to avoid blurred vision and to ease their manufacturing process including their sterile filtration.
Fig. 1. Change in viscosity of sodium hyaiuronate solutions with increasing shear rate.

7. International Journal of Pharmaceutics 327 (2006) 12–16
Stability of cosmetic formulations containing esters of Vitamins E and A: Chemical and physical aspects
International Journal of Pharmaceutics 327 (2006) 12–16

8. Introduction: Read from the article Aim: The aim of this study was to validate chemical and physical methods for stability determination in cosmetic formulations, using a gel-cream containing retinyl palmitate and tocopheryl acetate as a model. The results should also contribute to a better understanding of physical and chemical stability aspects of cosmetic formulations, mainly if they contain derivatives of Vitamins A and E.

9. Materials
Vitamin A palmitate (1,000,000 UI/g), Vitamin E acetate and Vitamin K1, Solvents,….
Methods
Gel-cream formulation,
Stability studies: Formulations containing vitamins A and E, were stored in PVC pots at 45, 37 and 25 ◦C and 75% relative humidity for up to 120 days.
Samples collected at 7-day intervals during the first 28 days and 60 and 120 days later for physical and chemical examination.
Chemical Stability testing for the vitamins using HPLC method and Calculations of shelf-life using the Arrhenius equation.

10. Rheological measurements Physical stability was assessed through rheological determinations performed in a Brookfield rotational rheometer with a cone-plate configuration, connected to a Brookfield software program. Rheological parameters were determined at 25 ◦C, using 0.5 g of each sample, 24 h after preparation and after different storage times. Rheogram curves constructed with ascendant and descendant segmentsm were obtained with rotation speeds increasing progressively (1–4 rpm) and gradually decreasing (4–1 rpm).

11. With the results obtained, values for consistency index (related to the system viscosity) and flow index (related to the system pseudoplasticity) were mathematically calculated by the Ostwald law: where τ is the shear stress, κ the consistency index, γ the shear rate, η is the flow index.

12. Results and discussion
Fig2. Quantification, expressed as logs of concentration values over time, of (A) : retinyl palmitate and (B): tocopheryl acetate, in formulations maintained at room temperature (25 ◦C), 37 or 45 ◦C with 75% relative humidity.

13. it is known that Vitamin A Retinyl palmitate had a lower stability than tocopheryl acetate (Fig. 2), indicating Vitamin A as the limiting factor in the calculation of product shelf-life. Furthermore, if retinyl palmitate decomposition leads to a complex mixture of products, its toxicity must also be considered. Thus, shelf-life determination is essential not only for efficacy aspects, but also to evaluate formulation toxicity.Thus, the safety and efficacy the system proposed in this study is acceptable only if the product is to be used in a restricted period of time.

14. Rheological measurements carried out in parallel with chemical studies represent a complete, rational and necessary approach to predict physical sample behavior during expected shelf-life. Rheological parameters indicated that addition of vitamins to the basic formulation did not compromise its structure but altered some of the rheological parameters as shown in rheogram (A) in (Fig. 3). The flow index in all formulations was below 1 indicating pseudoplasticity, which is a desirable rheological property in these preparations. It was not significantly altered despite a significant decrease in the consistency index after additions of retinyl palmitate and tocopheryl acetate.
Fig. 3. Formulation rheograms, 24 h after preparation at room temperature.
Formulations containing or not vitamins were compared in both time periods.

15. physical alterations are more prominent in formulations with added vitamins. Accordingly, Fig. 3B illustrates alterations of physical stability in the formulations containing vitamins, such as thixotropy, in addition to flow and consistency indexes.
Fig. 3. Formulation rheograms 120 days after preparation (B) at room temperature.
Formulations containing or not vitamins were
compared in both time periods.

16. This instability was not seen in the formulations without vitamins, suggesting that vitamin instability affected the formulation physical Integrity. Rheological parameters were determined and compared in formulations kept at different temperatures after 15% of the Vitamin A was degraded. Results are shown in Fig. 4 and Table 3. Rheological characteristics of formulations with approximately 85% of retinyl palmitate at all storage conditions were similar. It is concluded that accelerated physical stability studies by rheological measurements were also validated.

17. Although flow indexes were not altered by thermal stress consistency
indexes increased significantly (Table 3). It is widely known that consistency indexes normally decrease during storage, indicating instability, but in our results the consistency index increased. It is possible that this was due to the interaction of retinyl palmitate and polyacrilamide, the vehicle polymer.
Table 3: Consistency (CI) and flow index (FI) values determined in formulations 24 h after preparation and after 15% degradation of retinyl palmitate
Fig. 4. Formulation rheograms after 15% degradation of Vitamin A. Analyses were performed after (1) 77 days at 25 ◦C, (2) 21 days at 37 ◦C and (3) 14 days at 45 ◦C.

18. Conclusion It is concluded that the results in the present study validate chromatographical and rheological methods for analysis of gel-cream stability. Rheology measurements are simple and effective means to compare properties over time and HPLC furnishes accurate quantitative data on different substances added to complex matrixes. In addition, the results contribute to the understanding of cosmetic stability in formulations containing retinyl palmitate and tocopheryl acetate and confirm that chemical and physical stability must be evaluated at the same time since they seem to have related effects.