Cellulose derivatives such as Hydroxypropylmethylcellulose (HPMC) are widely used as thickness, binding agents, emulsifiers and stabilizers in the various oral and topical pharmaceutical preparations. HPMC has possess the special characteristics for control release drug preparations and its applications based on the four features i.e. surface activity, film forming ability, the capacity to form thermal gels that convert to liquid on cooling and efficient thinking. Moreover, HPMC solution changes in to gel form when it is heated at temperatures between 50 - 90èC. Therefore, it is necessary to study the rheological properties of HPMC at various concentrations.
The Haake VT-500 rheometer was used for the determination of the rheological properties and thixotropic behavior of Hydroxypropylmethylcellulose (HPMC) at various concentrations i.e. 2%, 4%, 8%, 12% and 14%. It has been observed from the results of the Haake VT-500 Rheometer that only 1% of HPMC solution showed Newtonian fluid properties, whereas the remaining concentrations of HPMC i.e. 2%, 4%, 8%, 12% and 14% have demonstrated pseudoplastic behavior. The viscosity of the pseudoplastic fluids can not be determined by single value of a graph because these HPMC solutions used in the experiment exhibit pseudoplastic flow and the consistency for these flows.
The fresh sample of 2% HPMC showed high amount of disentanglement upon applying of shear rates. This was followed by the slow reuniting of the polymer chains of HPMC solution when the shear rates were steadily decreased. This results in a broader hysteresis loop in the graph. Hysteresis loops become steeper in case of 4% and 8% of HPMC solutions due to the quick Brownian motion whereas, the rheogram of the 12% and 14% HPMC solutions give a linear line indicating the false Newtonian flow.
U-Tube and Falling sphere viscometers were also used to determine and compare viscosities of 1% HPMC solution. But these instruments have limitations and can not be used for the pseudoplastic fluids.
In conclusion, 1% of HPMC solution showed Newtonian behavior and others higher concentrations observed exhibit seudoplastic shear-thinning flow. Furthermore, 2% of HPMC solution showed a broader hysteresis loop and hence have more thixotropic effect as compare to other higher strengths. Finally, the application of the rheological properties of HPMC can be used in various pharmaceutical preparations for better outcomes.
Hydroxypropylmethylcellulose (HPMC); Rheological-properties; Newtonian; Non- Newtonian; Pseudoplastic; Thixotropy; Brownian motion; Rheometer
Rheology is the term used to describe the flow of liquids and deformation of solids under stress (Rawlins, 1984). It is defined as a study of the flow properties and deformation of materials (Martin et al., 1993). Viscosity is the important parameter of expression of the resistance of a fluid to flow. The fundamental principals of rheology are used in the formulation and analysis of various pharmaceutical products such as pastes, suppositories, emulsions, lotions, creams and tablet coating. Consistency and smoothness are the important qualities for the preparation of lotions, cosmetic creams and pastes which can be maintained and analyzed by the applications of rheology (Martin et al., 1993).
Various cellulose ether derivatives derived from cellulose are water soluble polymers and used in the food and pharmaceutical industries for a long period. These polymers have advantages of non- toxic nature, flow controlling capabilities, ability to behave as emulsifier and colloidal stabilizers and also exhibit biological properties which make them choice of biomedical applications (Fatimi et al.,2008).
Hydroxypropylmethylcellulose (HPMC) is a cellulose derivative polymer and also known as Hypromellose. Basically, HPMC is a methylcellulose modified with propylene glycol ether groups in small amount attached to the anhydroglucose of the cellulose (Fatimi et al., 2008). HPMC is a white or creamy white colored granular or fibrous, tasteless and odorless powder (Kibbe, 2000). It is soluble in cold water and form a viscous colloidal solution. Moreover, HPMC solution changes in to gel form when it is heated at temperatures between 50 - 90°C (Chen, 2006).
Hydroxypropylmethylcellulose (HPMC) is widely used in the various oral and topical pharmaceutical preparations, Food products and has good mechanical and non toxic properties. HPMC has possess the special characteristic for control release drug preparations and its applications based on the four features i.e. surface activity, film forming ability, the capacity to form thermal gels that convert to liquid on cooling and efficient thinking. These properties are mainly due to the strong hydrophobic zones of the methyl substitutes with backbone of cellulose and hrdroxypropyl group which are hydrophilic in nature (Perez et al., 2006)).HPMC is widely used as a thickeners, flow and texture enhancers, emulsifiers, stabilizers and thixotropic agents (Clasen and Kulicke, 2001).
HPMC is used in both, oral and topical pharmaceutical formulations. It is mainly used as binder, extended release matrix former and film coating in oral formulations. Concentrations of between 2%-5% w/v may be used as binder in dry or wet granulation of tablets and 2-20% concentrations used to form film coating tablets (Kibbe, 2000; Harwood, 2006).
It is also used in tropical formulations such as ophthalmic preparations, ointments and tropical gels (Kibbe, 2000; Harwood, 2006). It is mainly used as the thickening agent (0.45 -1% concentrations) in ophthalmic preparations such as artificial tear solutions and eye drops and stabilizing, emulsifier and suspending agent in other formulations such as ointments and gels. It is also used as moisture retention and oil reduction in food products and as stabilizer and emulsifiers in cosmetics (Kibbe, 2000; Harwood, 2006).
Many studies have been conducted to find out the properties of the HPMC. A study demonstrates that Cellulose ethers like methylcellulose (MC) and its derivative hydroxypropylmethylcellulose (HPMC) have acquired the unique property of reversible thermogelation. HPMC get completely hydrated in solution form and it results in little polymer- polymer interaction. An initial fall in viscosity is noticed when temperature is increased. It is mainly due to the decrease in the proportion of hydration water. When temperature reached at optimum level, there are significant polymer-polymer interactions instead of polymer-solvent interactions due to dehydration. As a result, HPMC converts from solution to gel and this process is completely reversible on cooling i.e. gel revert to solution form having its original consistency. However, the strength of the gel formed and the temperature at which gel formation occurs are depend on the molecular weight, concentration, presence of electrolyte, and degree and type of substitution of the gum (Liu et al., 2008)
Chemically, HPMC is a cellulose derivative consisting of a linear homopolymer backbone made up of D- glucopyranose units linked by ß1-4 glycosidic bonds in which hydroxyl groups of anhydroglucose are substituted by hydroxypropyl and methyl group. Moreover, HPMC aqueous solution shows a characteristic of reversible gel formation with temperature. This is mainly due to the hydrophobic interactions and also clouding precedes gelation (Silva et al., 2008).
HPMC have good swelling properties and compression characteristic which provides a high degree of drug loading as compared to the other polymers. Therefore, HPMC matrix start swelling in the presence of water and make a protective gel around the tablet content resulting to a sustained release of drug (Liu et al., 2008).
A rheogram is used to describe the flow properties of a given material and also known as flow curves or consistency curves. It is a plot of shear rate G versus shear stress F (Martin et al., 1993). The viscosity of HPMC solution decreases with increasing rates of shear. Newtonian systems follow a simplest form of a flow curve and show a straight line passing though the origin. The viscosity remains constant and do not show any change with the rate of shear. Therefore, a single reading of viscosity from the shear stress at any given shear rate can illustrate the flow properties of a Newtonian fluid (Martin et al., 1993).
On the other hand, the scenario is opposite in Non- Newtonian systems such as HPMC solutions. Non - Newtonian flow demonstrates the non linear curve throughout the all ranges of F values. The slope of the curve gradually decreases with increasing rate of shear. The viscosity is derived from the slope and apparently decreases with the increase in the shear rate F (Marriott, 2002).
Plasticity is the simple type of non- Newtonian behaviors showing the linear line only at values of shear stress F. Pseudo plastic flow represents the shear thinning and slope increasing with shear stress and dilatants illustrate the shear thickening and slope decreases with shear stress F. The pseudo plastic nature of flow is mainly due to the progressive breakdown of the structure in the liquid medium by increasing shear. This results in reforming of the structure by Brownian motion (Schott, 1995).
Furthermore, thixotropic system shows a hysteresis loop curve and increasing shear stress curve is not super imposable on the decreasing shear stress curve (Martin et al., 1993). Brownian motion tends to regain the structure back when shear rates are reduced in a time intervals. In other words, Thixotropy may be defined as 'an isothermal and comparative slow recovery, on standing of material, of a consistency lost through shearing. Thixotropy rheograms can be valid to shear thinning systems (Martin et al., 1993). The randomly coiled entangled polymer chains of HPMC tend to disentangle and align in the direction of flow due to shear rates. This results in reduction of viscosity. Furthermore, dissolved polymer chains can get disentangled and well aligned in the direction of flow when high shear forces are applied and this lead to completely breakup of structure. At last, there is no structure remaining for further breaking on applying high shear rates. However, some liquids show false Newtonian flow behavior by giving linear curve. This is mainly due to the no structure break down occurring when low shear rates are applied (Schott, 1995).
In this experiment, the Haake VT-500 rheometer was used to determine the flow properties of different prepared HPMC concentration solutions at constant temperature. However this rheometer had a disadvantage of fixed shear rates for higher concentration HPMC solution. In addition, the use of U-Tube and Falling sphere viscometers was also done though their use is limited only to Newtonian flow liquids (British Pharmacopoeia, 2008).
The objective of this experiment was to determine the rheological flow properties, thixotropy behavior and time dependence for the different concentrations of HPMC solution to reform due to changes in the rates of shear.
Materials and Methods
- Hydroxypropylmethylcelluse (HPMC), Batch Number MM93062572E, supplied by Colorcon, Dartfort.
- Distilled water was used for making different concentrations of HPMC
- Haake VT-500 version 01_PN/TW Rheometer.
- U-Tube viscometer, 300mm length, size D, Model Number BS/U
- Falling sphere viscometer, 220ml capacity, standard size.
- Weighing Balance, Précisor 180A, to weigh HPMC
- Weighing Balance, Précisor 125
- Six 500ml beakers
- Six 250ml Volumetric flask
- 250ml Measuring Cylinder
- Magnetic stirrer
- Preparation of different concentrations of HPMC
- Rheology Analysis using HAAKE VT 500 Rheometer
- Viscosity Analysis
The HPMC powder was weighed according to the required concentration and mixed in distilled water for making different concentrations i.e. 1%, 2%, 4%, 8%, 12% and 14%.
These solutions were prepared in beakers and mixed with the help of a stirrer. To avoid chances of errors, every sample, beaker and volumetric flask were labeled according to their respective concentrations i.e. 1%, 2%, 4%, 8%, 12% and 14%.
The different weighed HPMC powder samples were mixed in about 200 ml of distilled water and then followed by vigorously stirring with the help of a magnetic stirrer and kept at waterbath for fast dissolution. The temperature was increased to about 70°C in water bath to enhance dissolution.
When HPMC powder dissolved completely in the beaker, the volume is made up to the 250ml using distilled water in a volumetric flask or measuring cylinder.
These sample solutions of different concentrations were kept at 25°C in the water bath for 30minutes for equilibrium before the rheological experiment. The readings of rheological measurement were taken for the fresh solutions of each concentration and then they were stored in the lab for one week. Furthermore, same procedure was again conducted for taking rheological measurements for these solutions after a week.
Each concentration was prepared in duplicate in the next week using the same procedure mentioned above in the next week. The same readings were taken for each concentration after two week as well.
The Rheological measurements were taken using HAAKE VT 500 rheometer.
The substance name and the sample number were entered using the key board.
The samples of different concentration were placed in the water bath and allowed for 5-10 minutes at 25°C for equilibrium during experiment. This also minimizes sample dehydration and degradation during experiment and gives true rheological measurements
The test samples were individually lowered into the immersion sensor carefully using the button on the side of the Haake VT-500 rheometer and leaving approximately 1-2 mm of sensor above the level of sample, on the already turned-on ready rheometer and rheological measurements taken.
This was followed by pressing 'Zero' button on the Haake computer key board and space bar on the key board to run the test. There is a need to wait for the test to finish.
Then 'Space' bar was pressed to continue, when the test completed. 'Enter' key was pressed for print of the observations.
Finally, sensor was removed carefully from the sample and cleaned with blue tissue paper. The further readings were taken by entering 'Measure' on the menu and following the same procedure again.
The measurements were performed over constant fixed increasing and then decreasing shear rates ranging from 0-150 s-1 over a time of 1.02 minutes, with instrument pre-set routine of 10 segments.
Prints of readings were obtained in tabular form consisting of shear rate - D [1/s], shear stress - Tau [Pa], Dynamic viscosity - Eta [Pas], time [min] and temperature [°C].
Rheological measurements were then repeated on the same samples after storing the sample for one week and duplicate samples of same concentration. The graphs were plotted by taking the appropriate readings to compare the rheological properties.
Apart from Haake VT-500 rheometer for the viscosity measurements, U-tube and falling sphere viscometers were also used for comparisons the viscosity of the HPMC solutions.
- U-Tube viscometer
- Falling Sphere Viscometer
This apparatus is mainly used to determine viscosities of Newtonian liquids. In this experiment, viscosity was determined by measuring the time required for the liquid to pass between the two marks above and below the tubes bulb as it flows by gravity through a vertical capillary tube. Temperature was maintained at 25°C during experiment for equilibrium (British Pharmacopoeia, 2008).
Experiment was repeated three times and average of three reading was taken to minimize errors.
Density of the Sample:
A 50ml of empty volumetric flask was placed on a weighing balance - precisor 125. Its weight was torn off and then it was filled up to 50ml mark with 1% HPMC solution. Three readings for mean weight were recorded.
Falling sphere viscometer is only recommended for the determination of viscosities of Newtonian liquids (British Pharmacopoeia, 2008).
However, the time taken for the sphere to fall in 1% HPMC from the upper ring marks to the lower ring marks was very small duration and did not give any significant value for overall results. Due to this disadvantage, Falling sphere viscometer was not used further used to determine the viscosity of 1% HPMC solution. Another limitation of this viscometer is that it can only used for Newtonian liquids and other concentrations of HPMC solutions were shown Non- Newtonian flow behavior.
Results and Discussion
- Determination of flow behavior using Haake VT-500 Rheometer
- Newtonian Flow Properties
- Pseudoplastic Flow Properties:
- Thixotropy behavior and Reformation of gels
It has been revealed from the results of the Haake VT-500 Rheometer that only 1% of HPMC solution showed Newtonian fluid properties (Fig.1).
The line graph of 1% HPMC solution demonstrated that rate of flow is directly related to the applied stress of a liquid and this dynamic viscosity is not depend upon the shear rate of a liquid i.e. a characteristic of Newtonian solutions (Marriott, 2002). In this graph, same pattern was seen in the sample for fresh readings and after a week readings.
However, there are some asymmetric patterns seen in the graph which interpret the linear line of the graph. This may be due to the errors in the preparation of sample solution, storage conditions for a week, variation of the temperature from 25°C equilibrium temperature and mistake in operating the rheometer. But it is well documented that 1% of HPMC solution shows the Newtonian flow (Martin et al., 1993). Therefore, these errors did not influence the main results. Moreover, the trend lines for the both readings of fresh and after a week showed a linear line and proved a Newtonian behavior of 1% of HPMC solution.
The remaining concentrations of HPMC i.e. 2%, 4%, 8%, 12% and 14% have shown non Newtonian flow properties in the table-2 at temperature maintained 25°C in this rheometer experiment.
It was also illustrated that shear rate is inversely proportional to the dynamic viscosity of the solution i.e. viscosity decreases with the increase in the shear rate. It can be seen in the table-1 and table-2. Moreover, the results proved that the viscosities decrease when shear rates increase although some readings have shown an unexpected pattern. But these readings have no effect on overall results.
It has been noticed from the results that these HPMC solutions used in the experiment exhibit pseudoplastic flow and the consistency for these flows usually start at the origins or approaches at the low rate of shear which result in the no yield value and non linear graph. Due to these changes, the viscosity of the pseudoplastic fluids can not be determined by single value of a graph.
The line graph of pseudoplastic liquids obtained due to the shearing action on long chain molecules of solutions i.e. Linear polymers. Therefore, disarranged molecules of the solutions normally start to align their axes in the direction of flow as shearing stress is increased. These changes decrease internal resistance of the materials and permit a high rate of shear at each consecutive shear stress. Moreover, most of the solvent linked with the molecules may be released which result in an efficient lowering of the concentration as well as the size of the dispersed molecules. Finally, it results in decrease in the viscosity (Martin et al., 1993). This was further supported by the evidence that the water molecules also play as a lubricant and result in the HPMC solution to make slippery and show more pseudoplastic flow behaviour (Chen, 2006).
The comparison of table 2 and table 3 clearly demonstrated that the viscosities were also shown changes in the readings taken of the fresh samples and the week after storage at different concentration using rheometer. The shear- platic property can be seen in the Figure 2 and Figure 3 where 2%, 4%, 8%, 12% and 14% HPMC solutions follow the same behavior in more or less extent.
Pseudoplastic materials have shear thinning system and they have lower consistency at any rate of shear on the down curve as compared to the up curve. Finally it resembles as a gel at rest. This result in the breakdown in the structure and not allow to reinform immediately when stress is removed. This phenomenon is called as a thixotropy. It exhibit shear thinning and it is mainly due to the competition between the disconnection of entangled links among dissolved macromolecules or the split of Vander Waals forces among dispersed particles by shear, and the restoration of such links by Brownian motion. (Schott, 1995). These pseudoplatic materials transformed from gel-to-sol and exhibit shear thinning. In this way, structure start to change again and random Brownian movement restore the consistency of material. The previous history of the sample has a great role in the rheogram of the thixotropy materials. The extent of thixotropy can be analyses from the area of the hysteresis loop in the rheograms obtained (Martin et al., 1993).
The above line graph shows that fresh sample of 2% HPMC showed high amount of disentanglement upon applying of shear rates. This was followed by the slow reuniting of the polymer chains of HPMC solution when the shear rates were steadily decreased. This results in a broader hysteresis loop in the graph. This can be clearly seen in the figure-4 for 2% HPMC fresh solution.
Another reason can be the vigorous stirring during preparation which results in the breaking of the structure deeply and allow more displacement of the molecules from structure. These consequences also lead to the generation of slow structure during decrease of stear rate in the rheogram.
When the readings were repeated after one week and two week, it has been revealed the hysteresis loop area was significantly decreased as compare to the fresh solution. This is mainly due to the reforming of the polymer molecules by Brownian motion the changes in the loop prove reformation of solution over time of one week and two week. However, there was not considerable difference seen in the hysteresis loop of the 1% HPMC solution after 1 week and 2 week.
The same results can be observed in the Figure-5. This shows that hysteresis loops become steeper in case of 4% and 8% of HPMC solutions. This is mainly due to the quick Brownian motion.
In the figure 6, the rheogram of the 12% and 14% HPMC solutions give a linear line indicating the false Newtonian flow. It mainly due to the low shear rates of the rheometer and unable to effect any structure split at the high concentration solutions (Schott, 1995). However, Haake VT-500 rheometer has limit in testing the thixotrophy of high concentrations of polymers such as HPMC.
Overall, it can be illustrated that the solutions seem not to have reformed completely to their original molecular structure after one week and two week stored sample results as compared to the fresh solutions. This is effectively seen in the 2% and 4% HPMC solutions. Moreover, there is not significant difference seen in the thixotropy behavior after one week and two week storage.
- U-Tube Capillary Viscometer
- Falling sphere viscometer
This type of viscometer is most commonly used for Newtonian solutions. The viscosity of Newtonian liquids can be calculated by measuring the time taken for a liquid to pass from upper mark to lower mark through a capillary tube under the influence of gravity (Martin et al., 1993).
In this experiment, the only 1% HPMC concentration showed the Newtonian flow behavior. Hence, only 1% HPMC concentration viscosity was calculated and compared to that obtained from Haake's VT-500 rheometer. Calculation of Dynamic viscosity, ?, of 1% HPMC can be seen in Table 4.
The nearest reading that matches 2.343 mPas with that from Haake rheometer reading is 2.570 mPas, when the shear rates were 149.85 s-1 (Table 2).
The viscosity can be measured with U-tube viscometers at only one time with an average value of the shear rate (Schott, 1995); however the shear rates are not a fixed constant in the Haake rheometer. Therefore the average of viscosities taken from Haake's rheometer could not be compared with the value of viscosity from the U-tube viscometer.
This viscometer was also tested on 1% HPMC solution but, the time taken for the sphere to fall in 1% HPMC from the upper ring marks to the lower ring marks was very small duration and did not give any significant value for overall results. Therefore, this method was not further used for the other higher concentrations of HPMC solutions. Moreover, this method is not suitable for pseudoplastic materials which show changes in their consistencies (Martin et al., 1993).
This experiment was conducted to determine the rheological flow properties, thixotropy behavior and time dependence for the different concentrations of HPMC to reform due to changes in the rates of shear.
The results illustrate that only 1% HPMC concentration shows the true Newtonian behavior and it is well documented that only 1% of HPMC solution represents Newtonian flow properties. In addition, 2% and higher concentrations of HPMC have shown pseudoplastic flow behavior. The higher concentrations show decrease in the viscosity with the increase in the shear rate and, also, decrease when shear rates increase.
The thixotropic study demonstrates that 2% of fresh HPMC solution has shown more thixotropic behavior and generate a broader hysteresis loop in the graph as compared to 4% and 8% of HPMC solutions. This is mainly due to the high amount of disentanglement of molecules upon applying of shear rates and took longer to reform.
The rheogram of the 12% and 14% HPMC solutions give a linear line indicating the false Newtonian flow. The molecular structure to be deformed due to the low shear rates of the rheometer and unable to affect any structure split at the high concentration solutions
The application of the rheological properties of HPMC can be used in various pharmaceutical preparations i.e. oral preparations, tropical products and ophthalmic preparations. Moreover, this is used in food products at large scale. Therefore it is particularly significant to determine and apply the rheological properties for better outcomes.
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