Development and Evaluation of Elementary Osmotic Pump Tablet of Tizanidine Hydrochloride

Introduction

The oral drug administration system is the most popular way for administering pharmaceuticals because of its simplicity, as it is regarded more simple and less complicated, for its cost effectiveness, patient acceptance, and also because it provides the largest active surface area compared to any type of delivery system.¹ A controlled release dosage form releases one or more drugs in a planned sequence for a set period of time, either systemically or locally at a specifically targeted organ. The oral drug delivery systems deliver a drug at a therapeutically effective rate to a desired site, modulating GI transit time and minimizing first pass elimination. It maintains optimal and effective drug concentration levels for a longer period of time with less dosing frequency and side effects.²

Osmotic pumps mainly work on the principle of osmosis which is defined as net movement of solvent from the region of low concentration to the region of high concentration. The osmotic pressure of solutions with the same solvent and solute system is proportional to their respective concentration. As a result, the osmotic drug delivery system can achieve a constant osmotic pressure, i.e. a constant influx of water. The drug release in these systems is controlled by physiological factors in the gastrointestinal tract (GIT).³

Although 60-80% of drugs are released at a constant rate from Elementary Osmotic Pump, a lag time of 30-60 minutes is observed in majority of cases as the system hydrates before the beginning of zero-order distribution. These devices can administer drugs that have a modest water solubility.^4,5

The osmotically active substance is surrounded by the rate-controlling semi-permeable membrane in the Elementary Osmotic Pump (EOP) system. The creation of a saturated solution of drug within the core is caused by osmotic imbibition of water, which is delivered at a controlled rate from the delivery orifice in the membrane. As a result, this approach is appropriate for the administration of pharmaceuticals with a moderate water solubility.⁶

The mechanism involved in elementary osmotic pump is that, the pump contains the tablet core material which is enclosed by semi-permeable coating membrane and it is drilled at the centre of the semi-permeable membrane to generate a small delivery orifice within its outer surface. When it comes in contact with water, an osmotic pressure is established inside the core material with the help of an osmogenic agent and the osmogens imbibe the water inside the core of the tablet through the semi-permeable membrane (SPM) coating. This raises the hydrostatic pressure inside the tablet, forcing out the saturated drug solution through the film’s aperture.⁷

The controlled rate of drug delivery through the orifice is given by

dm/dt = (dv/dt) C_S

Where,

dm/dt = Rate of drug delivery from osmotic pump (mg/h)

dv/dt = Volume flow rate of water into the core (cm³ /h)

C_S = Drug concentration (mg)

Tizanidine HCl is an imidazoline derivative that is structurally similar to clonidine and adrenergic agonist with muscle relaxant property. Tizanidine is a centrally acting α-2 adrenergic agonist or receptors in the central nervous system (CNS), which inhibits presynaptic release of norepinephrine thereby increasing the inhibitory effect on alpha motor neurons and gamma motor reflexes. Tizanidine exerts some activity at the postsynaptic excitatory amino acid receptors and imidazoline receptors which may contribute to the overall reduction in facilitation of spinal motor neurons.^8-10

Tizanidine HCl comes under biopharmaceutical classification system (BCS) class II, with oral bioavailability approximately 40% (CV=24%) the elimination. Half-life is 2.5 hours (CV=33%) and roughly 95% of the dose is metabolized. Their steady state concentration reaches within 24-48 hrs.^11-13 Therefore due to the low bioavailability of Tizanidine hydrochloride (TZN HCl), the present work was planned to prepare sustained drug delivery approaches in the form of osmotic pump using different osmogens strived to increase their bioavailability.

Materials and Methods

Materials

Viswa Laboratories Private Limited, Pune, provided Tizanidine Hydrochloride USP as a gift sample. Loba Chemie, Mumbai, provided microcrystalline cellulose, polyvinyl pyrrolidone (PVP K30), magnesium stearate, isopropyl alcohol (IPA) and cellulose acetate. SD Fine Chem Limited, Mumbai, provided potassium chloride, talc, PEG 400, acetone, hydrochloric acid, potassium dihydrogen phosphate and sodium hydroxide. Lactose was purchased from Mumbai-based Hi Media Laboratories Pvt. Ltd. Fisher Scientific in Mumbai provided the sodium lauryl sulphate. Sisco Research Laboratory in Maharashtra provided the sodium phosphate tri-basic dodecahydrate. Analytical grade chemicals, reagents and components were utilized.

Compatibility studies for the drug-excipient

The Fourier Transform Infra-Red (FTIR) analysis was carried to determine any kind of drug excipient interactions. The Potassium bromide (KBr) pellet method was used to develop IR spectrum of drug and excipients. Then the KBr was dried in hot air oven at 60°C for 1 hr. The samples were prepared by mixing it thoroughly with potassium bromide. Each excipient was mixed thoroughly with drug separately and these mixtures were then placed in a scanning slot of Fourier Transform Infra-Red (FTIR) spectrophotometer and scanned between the range from 4000 to 400 cm^-1 to obtain FTIR spectrum of drug. Then the spectrum was compared with the spectrum of reference standard.¹⁴

Preparation of osmotic pump tablets

The preparation of osmotic pump tablet of Tizanidine HCl involved two steps which includes

Step 1: Preparation of osmotic pump core tablets

Step 2: Coating of tablets

Preparation of Core Tablets

The wet granulation process was used to develop elementary osmotic pump of Tizanidine HCl core tablets. All the ingredients were accurately weighed. Tizanidine HCl was mixed with potassium chloride, PVP, lactose, sodium lauryl sulphate and microcrystalline cellulose. Further this powder was triturated together in a mortar sequentially or the contents were blended for 15-20 minutes to get a homogeneous mixture. The wet mass was passed through sieve #22 to produce granules. Further the granules were dried in hot air oven at 50°C for 2 hours to get dried free flowing granules of Tizanidine HCl. The granules were then taken out of the oven and lubricated with magnesium stearate and talc.¹⁵

The obtained dried granules were further evaluated for powder behavior and flow properties. Then, using single station Cadmach tablet punching machine with 8 mm die, the appropriate amount of granules were compacted into a tablet. Each tablet was limited to a total weight of 300 mg.

Characterization

Evaluation of pre-compression parameters

Angle of repose (θ)

The angle of repose can be used to calculate the fractional forces in a loose powder. It is defined as the highest angle feasible between a pile of powder’s freely sliding surface and the horizontal plane. The funnel method was used to determine the angle of repose.¹⁶

θ = tan^-1h/r

Where, θ = angle of repose

h = height of the pile

r = radius of the base of the pile

Bulk density (D_b )

Bulk density is the proportion of powder’s total mass to its bulk volume. It was calculated by weighing the powder and pouring it into a measuring cylinder, then recording the volume.^17-22 The bulk density was stated in gm/mL and was calculated using below formula,

D_b = M/V_b

Where, M= Mass of powder

            V_b = Bulk volume of the powder

Tapped density (d_t )

Tapped density is the proportion of powder’s total mass to its tapped volume. By tapping the powder to a fixed volume, the tapped volume was calculated.^17-22 It was stated in gm/mL and was calculated using below formula,

D_t = M/V_t

Where, M = Mass of powder

            V_t = Tapped volume of the powder

Carr’s index (I)

Carr’s index is also known as compressibility index. It describes how easily a substance can be induced to flow. It was calculated by measuring the powder’s bulk density and tapped density.^17-22 It was expressed in percentage and calculated using below formula,

Where, D_t = Tapped density of the powder

            D_b = Bulk density of the powder

Hausner’s ratio

The Hausner’s ratio is a measure of the ease with which powder flows. It is the ratio of tapped density to bulk density of particular powder or granules. The formula for calculating Hausener’s ratio is as follows:^17-22

Hausner’s ratio = D_t /D_b

Where, D_t = Tapped density of the powder

            D_b = Bulk density of the powder

Evaluation of post- compression parameters (Uncoated Tablets)

Hardness

The tablet hardness was determined using a Monsanto hardness tester. The tablet was held between two jaws, one fixed and the other one movable. The load was steadily increased until the tablet shattered. The load value at that location was used to determine the tablet’s hardness. The hardness was measured in kilograms per square metre.²³

Thickness

The tablet’s thickness and diameter were measured using a Vernier caliper. For determination of tablet dimensions, digital Vernier caliper has been used. The tablet was placed horizontally and vertically between two jaws of caliper and adjustable digital screen was moved until it touched the edge of tablet and the dimensions were reported in millimeters.²³

Friability

The tablet’s friability was tested using the Roche friabilator. Initially ten tablets were weighed and the total weight was noted. Further the tablets were poured into friabilator and was rotated for 100 revolutions. The weight of 10 tablets after the rotation was noted and using these two values, percentage friability was calculated.²⁴ The formula for calculating percentage friability is as follows

Weight variation

For determination of weight variation, firstly ten tablets were weighed separately. Then the average weight was calculated. In comparison to average weight, the deviation for individual tablets was calculated and percentage deviation was reported. The following formula was used to calculate the deviation and percentage weight deviation of each tablet from the average weight.²⁵

Coating of core tablets

Preparation of coating material

Five percent w/v cellulose acetate (5 gms) was carefully weighed and gradually mixed in 100 mL acetone using a magnetic stirrer. After thoroughly mixing the cellulose acetate, the required amount of plasticizer (PEG 400) was added to same solution and stirred for another 30 minutes to obtain a clear solution.²⁶

Procedure for coating of tablet by Dip Coating Method

The weighed core tablets were taken and tablets were dipped into 5% coating solution by holding the tablet with the help of forceps without dropping tablet into the coating solution. The dipped tablets were placed on a glass plate and air dried at room temperature after coating. The tablets were then repeatedly dipped four times until a weight increase of 5-7 percent was noticed. Before being subjected to additional assessments, the coated tablets were air dried and mechanically drilled for the orifice using a micro-needle of size 0.25 mm.²⁶

Evaluation of post- compression parameters (Coated Tablets)

Percentage weight gain

The percent weight increase was computed using the following formula utilizing the average weight of the tablets before coating (W1) and the average weight of the tablets after coating (W2).²⁷

Drug content

For determination of drug content, three tablets were selected randomly, weighed before and after coating. The coating polymer was removed and tablets were crushed in a mortar. The powdered tablet equivalent to 100 mg of Tizanidine HCl was taken in 100 mL volumetric flask and volume was made upto to 100 mL with pH 6.8 phosphate buffer solution. 1 mL of solution was withdrawn from primary stock solution and diluted to 100 mL with 6.8 pH buffer solution to give required concentration of 10 μgm/mL and the absorbance was measured by UV spectrophotometer.²⁸

In vitro drug release studies

In vitro drug release studies were carried out by using dissolution apparatus type II (Electro lab, Mumbai, India) at 50 rpm. The dissolution medium consisted of 750 mL of 0.1 N HCl (pH 1.2) for two hours and then the pH was changed to 6.8 by adding 250 mL of 0.2 M solution of tri-basic sodium phosphate dodecahydrate for the rest of dissolution study duration. It was adjusted if necessary, with 2 M hydrochloric acid or 2 M sodium hydroxide to a pH 6.8 ± 0.05. The temperature of the dissolution medium was maintained at 37±1°C and the dissolution studies were carried for 24 hours. At different intervals, appropriate volume from the dissolution medium was withdrawn and suitable dilution was made and absorbance was taken using UV spectrophotometer.²⁹

In vitro drug release kinetics

The kinetic studies for all the formulations were carried out using the in vitro release data obtained from dissolution studies. Kinetic studies were carried out using KINET DS 3 software. The release data was put into Zero order, First order, Korsmeyer peppas model and Hixon crowel equations. After the equation analysis, the highest regression coefficient value closer to one was considered as best fit model for the respective formulation and was reported.³⁰

Surface Membrane Morphology / Scanning Electron Microscopy (SEM)

SEM study was carried out for the optimized formulation to find out the orifice size, before and after dissolution. It was done by separating coating membranes of optimized formulation before and after the dissolution test and were examined for their porous morphology using scanning electron microscope by cutting them into segments. Then membrane was dried at 45°C for 12 hrs and stored between sheets of wax paper in desiccators before the examination. Then the membrane samples were sputter coated for 5-10 minutes with gold by using fine coat ion sputter and examined under scanning electron microscopy. After the analysis, the photographs were analyzed and recorded.³¹

Stability Studies

In order to determine the changes in in vitro release profile on storage, stability study of optimized formulation was carried out at 250 C ± 20 C (60% ± 5%RH) and accelerated conditions at 400 C ± 20 C (75% ± 5%RH). Samples were withdrawn at regular intervals during the study of 30 days and evaluated for different parameters.^32,33

Results

FTIR Spectroscopy

The FTIR Spectroscopy of drug and polymers are illustrated in figure 1.

Evaluation of pre-compression parameters

Evaluation of granules

Evaluation of post- compression parameters (Uncoated Tablets) 

Evaluation of post- compression parameters (Coated Tablets)

In vitro drug release studies

In vitro drug release kinetics

Stability studies for optimized formulation

Discussion

FT-IR spectroscopy

Using FT-IR spectrophotometer, the obtained spectrums of the pure drug, osmogen as well as drug with osmogen used in the formulations are shown in Figure 1. The major functional groups of Tizanidine HCl in FT-IR spectrum were aliphatic N-H stretching group observed at 3240.42 cm^-1, aromatic C-H stretching group at 2949.54 cm^-1, aliphatic C=N stretching group at 1602.49 cm^-1, aromatic C=C stretching group at 1506.73 cm^-1 , aliphatic C-N stretching group at 1065.73 cm^-1, aliphatic C-Cl stretching group at 708.06 cm^-1. The same functional groups were also present in the peaks and patterns of Tizanidine HCl, osmogen and Tizanidine HCl with osmogen. The drug had peaks in specific areas, indicating that it contains the appropriate functional groups. With the influence of polymers in physical mixtures, no such large alterations in the peak were observed. Thus, it suggests that the drug and excipient were compatible with each other and no drug excipient interactions were observed.

Evaluation of pre-compression parameters

Evaluation of granules

All the formulation granules were subjected for the physical characteristics such as Angle of repose, Bulk density, Tapped density, Carr’s index and Hausner’s ratio. Results are depicted in Table 4. Angle of repose values for all formulations ranged from 19.62° ± 0.16 to 23.470 ± 0.35, which was found to be within the normal range, thus indicating excellent flow properties. The bulk density was found to be in the range of 0.416 ± 0.001 to 0.454 ± 0.002 gm/cc, which is within acceptable limits. The tapped density ranged from 0.478 ± 0.013 to 0.512 ± 0.003 gm/cc, with results falling within the permitted range. Carr’s index was determined to be in the range of 11.37 ± 0.67% to 15.49 ± 0.68%. This indicates a good flow property. Hausner’s ratio was found to be in the range of 1.12 ± 0.011 to 1.18 ± 0.003 and the results were below 1.25 suggesting a good flow property.

Evaluation of post- compression parameters (Uncoated Tablets)

The weight of a single tablet was 300 mg and the allowable variance was 5%. The weight variation test revealed that the weight of all uncoated tablets were within the permissible range of 0.56% to 0.90% and the deviation was less than 5%. The hardness of uncoated tablets ranged from 4.86 ± 0.04 to 5.13 ± 0.16 Kg/ cm2 (acceptable range 4.5-5.5 Kg/cm² ), and they were determined to be nearly uniform and mechanically strong. Uncoated tablets had thicknesses ranging from 4.05 ± 0.13 mm to 4.28 ± 0.03 mm and were determined to be nearly consistent in thickness and compressive force. Uncoated tablet friability ranged from 0.37± 0.11% to 0.66 ± 0.02%, with all values under 1%, showing that tablets of all formulations had good compactness and strength to bear the force during the coating operation without breaking. All the results are shown in Table 5.

Evaluation of post- compression parameters (Coated Tablets)

The weight of a single tablet was 300 mg and the allowable variance was 5 to 7.5%. The weight variation test revealed that the weight of all coated tablets was within the allowed range of 0.08 ± 0.51% to 0.91 ± 0.07% and the weight variation deviation was less than 5%. After coating, the percent weight gain was determined to be between 5.51 ± 0.19 and 6.17± 0.07%. For coated tablets, the standard percent weight gain ranged between 5-7 and the result proved that the percent weight gain was within the acceptable limits. The hardness of coated tablets ranged from 6.53 ± 0.12 to 7.43 ± 0.15 Kg/cm2 (acceptable range 6-8 Kg/cm2 ) which were found to be almost uniform and possessed good mechanical strength. The thickness of coated tablets ranged from 4.31 ± 0.011 mm to 4.54 ± 0.09 mm, which were almost found to be in uniform thickness and with uniform compression force. The friability of coated tablets was ranging from 0.03 ± 0.004 % to 0.09 ± 0.005 % and all the values were below 1% indicating that the tablets of all formulations were having good compactness and strength to withstand the force during the coating operation without breaking. The drug content of coated tablets was found between 92.70 ± 0.32% to 98.61 ± 0.54%. The values were almost uniform and lie within the IP specifications of Tizanidine HCl i.e., 95% to 115%. All the results are shown in Table 6.

In vitro drug release studies

In vitro drug release studies were carried out in triplicates for all the batches, in which release data was examined for 2 hours in a 1.2 pH buffer and then for 22 hours in a 6.8 pH buffer. The drug release for all formulations ranged from 90.45 ± 0.99% to 97.27 ± 0.43% at the end of 24 hours. Among all the batches, the formulation F1 had the lowest drug release rate. The formulation F9 showed maximum drug release. Based on the in vitro drug release profile, the optimum formulation F9 was selected as the best among all the batches for further assessment. The results of drug release are shown in Figure 2.

In vitro drug release kinetics

The Tizanidine hydrochloride tablets in vitro drug release data were kinetically assessed using the Zero order, First order, Korsmeyer Peppas and Hixon Crowell models. KINET DS 3 Software was used to process the data for regression analysis. The highest regression coefficient (R2 ) values for all the batches showed that all batches followed Zero order release kinetics. The non-fickian release of the optimized formulation F9 was governed by zero order kinetics with an R2 value of 0.9768.

Scanning Electron Microscopy (SEM) analysis

When examined under a 100x magnified lens, the delivery hole was discovered to be 0.3 mm in diameter. The membrane’s surface structure was observed to remain intact before and after dissolution testing. Coated tablets had a glossy finish and the membrane appeared to be integrated and smooth, with no evident flaws. SEM micrographs of membrane surfaces after dissolution studies revealed that no pores had formed in the membrane.

Stability studies for optimized formulations

The tablets from formulation F9 (optimized formulation) were evaluated for physical appearance, hardness, friability, drug content and drug release after 15th and 30th day. The results were within the permissible limits. It was observed that coating membrane was devoid of any change in color or appearance and there was absence of any kind of spot on it. It was also noted that membrane was free of any kind of microbial or fungal growth or bad odor. No change in the smoothness of the membrane was observed. Thus, the developed formulation was found to be stable at room temperature 250 C ± 20 C (60% ± 5%RH) and accelerated conditions at 400 C ± 20 C (75% ± 5%RH).

Conclusion

A successful effort was made to develop an elementary osmotic pump tablet of Tizanidine HCl by using wet granulation technique. KCl was used as an osmogenic agent, MCC and lactose were added in various proportions. The physicochemical parameters like pre-compression and post-compression evaluations were performed as per pharmacopoeia standards and compatibility study was done by FT-IR method. The FT-IR analysis demonstrated that the osmogen and excipients were compatible with the drug. The pre-compression parameters and post-compression parameters were evaluated for all formulations (F1–F9) which were found within the standard range; the formulation F9 showed promising results. The drug content was consistent in all the formulations, showing that the drug was distributed evenly throughout the matrices. The release profile dissolution study was carried out for 24 hours with 0.1 N HCl (1.2 pH) for 2 hrs and 6.8 pH phosphate buffer for 22 hrs, yielding promising results for sustained release. Formulation F9, which contained KCl as an osmogen, showed the highest drug release rate, while formulation F1 showed lowest release rate. SEM studies confirmed that the size of orifice was good in all the formulations and there was no change in the surface of the membrane before and after the contact with aqueous environment and the orifice size at 100x showed 0.3 mm. The kinetic release models revealed that all formulations followed zero order kinetics. The final composition F9 was chosen for stability tests, which showed minor fluctuations in parameters even after a month, suggesting that F9 was stable and retained its original properties. Thus, the KCl at appropriate proportion acted as osmogenic agent. Thus, the elementary osmotic tablets can be successfully prepared with the help of osmogenic agents.

Conflict of interest

None

Acknowledgement

Authors are thankful to Dr. Vishnu Halnor, Viswa Laboratory Pvt. Ltd, Pune for providing gift sample of Pure Tizanidine HCl for research work. Special thanks to STIC, SAIF Cochin, Kerala for carrying out the SEM analysis work. Our grateful thanks to Hanagal Shri Kumareshwar College of Pharmacy, Bagalkote for providing the necessary infrastructure & facilities for this research work.