FORMULATION DEVELOPMENT OF ISOXSUPRINE HYDROCHLORIDE MODIFIED RELEASE MATRIX TABLETS

FORMULATION DEVELOPMENT OF ISOXSUPRINE HYDROCHLORIDE MODIFIED RELEASE MATRIX TABLETS

Ketan Patel*¹ and Mukesh C. Gohel ²

Dharmsinh Desai University ¹, Nadiad- 380 054, Gujarat, India

L. M. College of Pharmacy ², Ahmedabad-380 009, Gujarat, India

ABSTRACT:The objective of the present investigation was to study the effect of critical formulation parameters affecting release of isoxsuprine hydrochloride from matrix tablets using combination of polyethylene oxide (PEO) and dicalcium phosphate (DCP). The powder blend consisting of drug and excipients was analyzed for angle of repose, Carr’s index and Hausner’s ratio. The tablets were prepared by direct compression method. To assess the compressional behavior of the drug-excipient blend, the tablets were analyzed for friability and crushing strength. The in vitro drug release study was carried out in distilled water. The powder blend exhibited satisfactorily flow as measured by angle of repose, Carr’s index and Hausner’s ratio. The formulation ingredients showed satisfactory tableting properties (friability <1%, crushing strength ≥ 4 kgf).  The drug release was modified on addition of PEO and DCP. Addition of 5 to 25% DCP in the formulation of matrix tablets caused apparent difference in the drug dissolution in distilled water. However, the difference was insignificant as analyzed by analysis of variance (ANOVA) and similarity factor ( f₂). The drug release from the tablets was best explained by Weibull model. Unified Weibull model was evolved to predict drug release from the formulated batches. The findings of this investigation can be extended to industry to cut down the cost of formulation and to by-pass the existing patents employing hydrophilic matrixing agents, at least for selective drugs.

INTRODUCTION: Isoxsuprine hydrochloride is structurally a novel vasodilator ¹. The short biological half-life (5±2 hr) and the fast clearance make the drug, a suitable candidate for the development of modified release formulation.

Furthermore, the drug is required to be taken for a long period by the patients. The use of modified release formulation is associated with less nausea and dizziness at the initiation of therapy. Hence, to improve the patient compliance as well as to reduce side effects, the drug needs to be formulated in modified release dosage form.

Hydrophilic polymer matrix systems are widely used in oral modified drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance ^{2, 3}.

These dosage forms are designed to deliver the drug at a modified and predetermined rate, thus maintaining a therapeutically effective concentration of the drug in the systemic circulation for a long period of time and therefore reducing the frequency of dosing and improving patient compliance ^{4, 5}. Hydrophilic polymers such as hydroxylpropyl methylcellulose (HPMC), sodium carboxymethylcellulose, Carbopols^® and polyvinyl alcohol have been extensively examined in the formulation of modified release systems either alone or in combination with other release controlling agents ^6-10.

Drug release from matrix tablets is dependent mainly on the properties of active pharmaceutical ingredient and excipients. The most frequently used hydrophilic excipient in matrix tablets is HPMC. The wide spread use of HPMC is attributed to the fact that is available in various viscosity grades and it enjoys wide regulatory acceptance. The research and development scientists dealing with generic drugs are in search of a formulation/process that is not covered under patents. Literature search revealed that PEO has not been fully explored by scientists, at least for the newer drugs.

Polyethylene oxide (PEO) has been recently studied as a matrix forming polymer due to its availability in a range of molecular weight/viscosity grades, wide regulatory acceptance and unique swelling and erosion characteristics, which are utilized for modulating release of drugs with different solubility and doses. PEO hydrates rapidly and forms gelatinous barrier layer around wetted tablet when it comes in contact with water,. Drug release occurs by diffusion of active through gel layer and/or gradual erosion of gel exposing fresh surfaces containing drugs to dissolution medium. Diffusion is dominant mechanism controlling release of water soluble actives and erosion of matrix is dominant mechanism controlling release of water insoluble actives.

The use of water insoluble and non-swellable dicalcium phosphate (DCP) has not been explored in formation of matrix tablets. Hence, one of the objectives of this investigation was to explore the use of DCP. Dicalcium phosphate may provide less porous environment as compared to the use of water soluble excipient in a matrix tablet.

It is worthwhile to note that PEO undergoes quick gelling during aqueous granulation, especially when little excess water is added. Dicalcium phosphate is not sensitive to water and therefore it can be tried in wet granulation along with PEO in the formulations demanding the step of granulation to address the issues of flow and/ or compressibility.

The objectives of the present study were to prepare isoxsuprine hydrochloride modified release matrix tablets by direct compression and to determine the optimal levels of excipients such as PEO and DCP.

MATERIALS AND METHODS:

Materials: Isoxsuprine hydrochloride I.P., polyethylene oxide (PEO, Polyox WSR 303) and magnesium stearate were obtained as gift samples from Troikaa Pharmaceuticals Ltd. (Ahmadabad, India). Colloidal silicon dioxide (Aerosil 200) and butylated hydroxy toluene were procured from Evonik Degussa and S. D. Fine Chem. respectively.  Dicalcium phosphate was purchased from Innophos.

Preparation of Isoxsuprine Hydrochloride Matrix Tablets: Matrix tablets of isoxsuprine hydrochloride were prepared by direct compression method. Polyethylene oxide and magnesium stearate were sifted through 60 # screen. All the ingredients were blended in geometric fashion. Butylated hydroxy toluene was added in all the batches as an antioxidant. The blend was compressed to tablets by using a rotary tablet machine employing 5.55 mm FFBE punch (D tooling). The batch size was 2000 tablets.

Evaluation: All the powder blends were evaluated for Angle of repose, Carr’s index and Hausner’s ratio. Tablets were evaluated for friability, crushing strength and in vitro dissolution study with release kinetics.

• Angle of Repose: It was determined by funnel method. Accurately weighed powder blend was taken in funnel. Height of funnel was adjusted in such a way that tip of funnel just touches the apex of heap of powder. The powders were allowed to flow through funnel freely onto a clean surface. Diameter of powder cone was measured and angle of repose was calculated. According to USP, the flow property is graded as excellent if the value of angle of repose is in between 25 and 30^o.
• Carr’s Index and Hausner’s Ratio: The powder blend was transferred into a measuring cylinder and was tapped mechanically by raising the cylinder and allowing it to drop under its own weight using tapped density tester (Electrolab, ETD 1020) that provided a fixed drop of 14±2 mm at a nominal rate of 300 drops per minute. The cylinder was tapped 500 times initially and the tapped volume was measured. Tapped density was calculated by using tapped volume, which was used to find out the Carr’s index and Hausner’s ratio. Hausner’s ratio less than 1.25 indicates good flow properties while ratio greater than 1.5 shows poor flow of powder.
• Friability: One hundred tablets were loaded in friability tester (Electrolab Ltd.) after recording their weight. The drum was recorded at 25±1 rpm for 4 min and then they were weighed after screening. The percentage friability of tablet was calculated using the values of weight.
• Crushing strength: Crushing strength of the compressed tablets was measured employing tablet breaking force tester USP (Electrolab Ltd.) The equipment was put on ON mode and zero value was adjusted on display panel. The unit switch was set to Kgf. The guard cover was slided and the tablet was placed on the tablet platform. The plunger was driven by turning the knob. The point at which the tablet fractured (n=3) was recorded.
• In- Vitro Dissolution Test: Isoxsuprine hydrochloride release from tablets was determined in 500 ml water at 37±1°C. The paddle rotation speed was 100 rpm. Five ml samples were withdrawn at defined time intervals, and the same volume of water was replaced. Samples were subsequently collected at predetermined time. The samples were analyzed by using a double beam UV-VIS spectrophotometer (UV-1700, Shimadzu Corp, Kyoto, Japan) at a wavelength of 274 nm. Dissolution tests were repeated three times for all formulations and the percentage drug dissolved was calculated using standard calibration curve. The results of dissolution study were analyzed for kinetics and drug release.

RESULTS AND DISCUSSIONS: One of the objectives of the present study was to use direct compression as a method of manufacturing tablets since the current trend in the industry is to select a method that require simplified validation. The two important requirements for direct compression are good flow and good compressibility. Hence, the formulations were assessed for these two parameters. Wet granulation was not employed in the present study since the granulation step with aqueous fluid is very critical, demanding stringent control of variables, especially when PEO is used as a matrixing agent. .

The major objective of this investigation was to prepare modified release tablets isoxsuprine hydrochloride, which should release less than or equivalent to 25% drug in first hour and uniform drug release thereafter. Accordingly an ideal drug release at 1, 2, 4, 6, 8, 10 and 12 hr should be about 25, 31, 45, 59, 72, 86 and 100% respectively. A batch that showed least deviation from this profile was labeled as the most appropriate formulated batch.

Preliminary study was carried out by preparing a batch of 2000 tablets containing 30% of the drug and 70% of DCP. The powder blend showed poor flow (angle of repose 51^o) and the tablets exhibited low crushing strength (2.25 kgf). The probable reason for poor flow could be presence of small size DCP particles.  More than 90% drug was released in less than 1 hr, indicating the need of a release retardant such as hydrophilic matrixing material. Polyethylene oxide was used as a hydrophilic material in the range of 40 to 70%. These formulations are expected to release the drug at a flow rate due to swelling and gelling of PEO.

Piriyaprasanth and Sriamornsak reported that drug release at one hr sampling time was strongly influenced by flowability (Carr’s index and angle of repose) from HPMC matrix ¹¹. The investigators further reported that poor flowability may result in higher weight variation in tablet and lower tablet strength. Hence, in the present investigation, these evaluation parameters were included. The powder blends containing PEO showed excellent flow and good compressibility (see Tables 1 and 2).

Batches 1 and 2 were prepared employing 30 or 60% of the drug and the balance amount was PEO. The drug release was 84% in 12 hr (incomplete drug release) from the tablets containing 70% PEO (batch 1).  At higher level of PEO, the drug release was retarded probably due to better bonding between particles of PEO and resultant control of water uptake (dry core of tablet).

The other possible reason for incomplete drug release from the tablets containing 70% PEO could be increased resistance to diffusion of drug solution.  Hence, it was decided to reduce the amount of PEO in the succeeding trials. The tablets of batch 2 containing 60% drug failed to meet the criteria of crushing strength (3.5 kgf).

In the batches 3 to 5, five to twenty five percentages DCP was tried to achieve the target dissolution profile. The results shown in Table 2 reveal that the powder blends of batches 3-5 showed good flow and acceptable mechanical properties. The tablets were further tested for dissolution studies in water.

TABLE 1: FORMULATION OF ISOXSUPRINE HCL TABLETS

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