Formulation development of immediate release chlorpropamide tablets using directly compressible excipients

Diabetes mellitus is a major cause of morbidity and mortality worldwide. Chlorpropamide is an oral antidiabetic drug belonging to sulphonyl urea group, frequently prescribed in the treatment of type II diabetes mellitus. The present study was aimed on adopting cost effective direct compression method for the development of immediate release tablets of chlorpropamide by employing Avicel PH 102 and pregelatinized starch as directly compressible excipients. Each batch of tablets was evaluated for different pharmacopeial and non-pharmacopeial tests. All pharmacopeial tests were within the specified limits. Disintegration time was less than 15 min, except for one formulation. Dissolution results were satisfactory and within the range of 73 to 91% for all formulations. High performance liquid chromatography (HPLC) method was used to determine the drug content of each tablet batch. Assay was within the United States Pharmacopeia (USP) limit for three formulations. The present study concluded that chlorpropamide tablets can be successfully prepared by direct compression method. This technique reduces manufacturing cost by employing least number of excipients. Formulation F3 proves to be the best immediate release formulation because of its good physical attributes and assay results predicting to have improved bioavailability.


INTRODUCTION
Chlorpropamide (CP) is an oral glucose lowering agent belonging to sulphonyl urea group effectively used in the treatment of diabetes mellitus 2. It increases the secretion of insulin from pancreas by interacting with adenosine triphosphate (ATP) sensitive potassiumchannel receptors on the pancreatic cell surface.It also enhances the effect of insulin on liver.It has a molecular weight of 276.74 Da (Huupponen and Lammintausta, 1981).Figure 1 illustrate the structure of Chlorpropamide.
Recommended daily dose ranges from 250 to 500 mg.CP reaches the highest circulating levels in 2 to 4 h, as it is promptly absorbed in the gastrointestinal tract.CP is metabolized in the liver (80%), mainly via CYP2C9 and the metabolites are chiefly excreted in the urine (Arrigoni et al., 1987).Its biological half-life is 36 h.Due to the protracted elimination of the drug; the dose should be reduced by 50% in patients with renal impairment (Abe et al., 2011).Direct compression offers a number of advantages and considered to be the method of choice for the formulation of tablets over other manufacturing processes.Some distinguishing features of this method include cost effectiveness, suitability for moisture and thermolabile active pharmaceutical ingredients (API), faster disintegration and dissolution, etc. Disintegration or dissolution is the rate limiting step in absorption of poorly soluble drugs prepared by wet granulation.The tablets prepared by direct compression reveal relatively more rapid dissolution because the tablets disintegrate into drug particles that directly approaches the dissolution fluid (Jivraj et al., 2000;Rubinstein, 2000).The execution of direct compression formulation generally depends upon the use of appropriate excipients.Excipients compatibility with APIs, particle size distribution, binding capability and flow properties of powder blend are major designing features for directly compressible formulations (Bolhuis and Chowhan, 1996;Parrott, 1990).
These features are offered by a small number of directly compressible binders-fillers (Wade and Weller, 1994).Previous studies had shown that Avicel PH 102 showed excellent compact hardness because of its plastic deformation under pressure (Bolhuis and Chowhan, 1996;Lee et al., 2000).Avicel PH 102 showed better flow than Avicel PH 101, due to its larger particle size and the spherical particle shape (Bolhuis and Chowhan, 1996;Lee et al., 2000).Pregelatinized starch is a modified starch used as a binder, disintegrant and diluent in oral dosage forms.It shows enhanced flow and compression characteristics as compared to simple starch and used in dry-compression or direct compression processes (Iskandarani et al., 2001).
Diabetes mellitus is a major cause of morbidity and mortality globally.Literature shows that the incidence of type II diabetes has more than doubled in the last 30 years (Fox et al., 2006).Among other antidiabetic agents CP is a safe and low cost drug frequently prescribed for the treatment of type II diabetes mellitus.The present study was aimed to develop immediate release CP tablet by cost effective direct compression method.

Process of chlorpropamide tablets manufacturing by direct compression method
Tablets were manufactured by direct compression method employing single punch machine.Formulations were designed with varying percentages of excipients keeping the drug content constant (Table 1).The varying quantities of Avicel PH 102 and pregelatinized starch are summarized in Table 2.All the ingredients were passed through 20 mesh sieve separately, weighed accurately and blended in a polyethylene bag for 5 min excluding magnesium stearate.Magnesium stearate was added lastly and all ingredients were again mixed for further 5 min.The final blends were compressed directly using round shaped biconcave punches.Figure 1 Evaluation of tablet properties Each batch of tablets was evaluated for different pharmacopeial and non-pharmacopeial tests such as weight variation, hardness, thickness variation, friability, disintegration, dissolution and assay.Weight variation is a direct indicator of the dosage form uniformity. Therefore, weight of the tablet has to be routinely measured to ensure the proper amount of the drug in each tablet.Tablets (n = 20) were weighed individually by using electronic balance.Hardness of randomly selected tablets (n = 20) was determined by using digital hardness tester.The results are mentioned as mean ± SD.The thicknesses of twenty randomly selected tablets were determined by using vernier caliper and the data was analyzed to calculate mean ± SD.Tablet thickness also becomes important characteristics in counting tablet using filling equipment.Fifteen tablets of each formulation were weighed and subjected to friability studies.Percentage friability of the tablets was calculated by the following formula: Percentage friability = W 1 -W 2 / W 1 × 100 Where, W 1 = weight of tablets before testing and W 2 = weight of tablets after testing.Disintegration test was performed using basket rack assembly in 900 ml of distilled water maintained at 37 ± 2°C and the disintegration time was noted compared with the disintegration time which was noted.The dissolution test (n = 6) were carried out using USP dissolution apparatus II (paddle method) at 37 ± 0.5°C and 50 rpm in 0.1 N HCl acid.The drug concentration was measured using a UV double beam spectrophotometer at 230 nm (Pharmacopeia, 2005).

Pharmaceutical assay
Assay was performed on HPLC according to USP 28 (Pharmacopeia, 2005).The chromatographic procedure was carried out by using a stainless steel column (25 cm × 4.6 mm).The recommended mobile phase is a filtered and degassed mixture of equal volumes of acetonitrile and dilute glacial acetic acid.The detection was carried at a wave-length of 240 nm.The peak area of sample was compared with that of reference standard prepared having working strength of 0.005% using mobile phase.Potency of active drug was calculated by the formula: Average Peak Area of Sample × Conc. of Standard % A s s a y = × 1 0 0 Average Peak Area of Standard × Conc. of Sample

RESULT AND DISCUSSION
Immediate release tablets of chlorpropamide (CP) were prepared by direct compression employing directly compressible excipients.As the powder blend has good flow properties (Table 3).The tablets prepared showed less weight variation.Average tablet weight was in the range of 450.4 to 452.8 mg.Avicel PH 102 offered better binding capabilities with improved flow properties.Magnesium stearate was also added as lubricant to impart better flow properties of powder blend in reducing the chances of weight variation.Thickness variation of CP tablets was in the specified limit of ± 5%.Variation in average tablet weight and thickness is often governed by the flowability of the tablet content and filling of the dye (Davies and Newton, 1996).The hardness of the tablets should be within the acceptable limit.Hardness is an in process control test performed during manufacturing, depicting the compaction behavior of the material (Davies and Newton, 1996).Hardness is an in process control test performed during manufacturing, depicting the compaction behavior of the material (Davies and Newton, 1996).The hardness of the tablets should be within the acceptable limit.Too hard tablet may delay the disintegration and release of drug, however soft tablets may not bear shocks, during handling, storage and distribution (Davies and Newton, 1996;Huynh-Ba, 2009).Proper selection of the filler/binder and the applied compressional force are decisive factor for tablet hardness.A slight variation in the binder ratio in especially in directly compressed tablet can lead to common defects including chipping, lamination, capping and friable tablets (Peck et al., 1989).Avicel PH 102 was used as binder and filler to overcome these problems.The developed CP tablets have the hardness in the range of 8.47 to 8.87 kg.The friability was also determined and found to be less than 0.7%, demonstrating good mechanical strength (recommended limit is < 1%) (Table 4).Tablet should be assessed for friability to ensure that they are able to sustain their physical integrity when subjected to mechanical shocks during manufacturing and transportation (Huynh-Ba, 2009).Oral tablet should be disintegrated within the specified limits to release its drug content.The choice of suitable excipients should be carefully executed to get desired disintegration time (Vadas et al., 1984).Most of the developed CP tablets were disintegrated within 15 min except formulation F1 which disintegrated in 25 min (Table 4).Pregelatinized starch was used in the formulation as disintegrant and improves the disintegration of the CP tablet.Another researcher also observed the reduction in the disintegration time of tablets with increase in quantity of starch (Mohammed, 2013).
Dissolution tests were performed using USP dissolution apparatus II in recommended medium that is, acetyl buffer and purified water.For proper absorption, drug release from dosage forms has to be carefully observed.The percentage drug dissolved in 30 min was in the range of 73 to 91%.The drug contents was uniform across all the developed batches of CP tablets and found within the pharmacopeial limits (that is, 90 to 110%) USP 28 (Table 5).The chemical assay was performed using HPLC as mentioned in USP official monograph of CP.HPLC gave accurate and reliable results (Fong, 1991).The pharmacotechnical attributes of developed CP tablets were compared and it was found that F3 is the optimal formulation, with short disintegration time, better dissolution and drug content near to 100%.Development of oral tablets involves choice of appropriate technique and excipients.In case of immediate release tablet, efficient disintegrants fight against the effectiveness of tablet binder and compressional forces and immediately release the drug content from the tablet.The present study concluded that the combination of pregelatinized starch and Avicel PH 102 employing direct compression provided the formulation to release and sustain the integrity of tablet.

Table 2 .
Percentage composition of chlorpropamide tablets

Table 3 .
flow properties of the powder blends.

Table 4 .
Physical testing of chlorpropamide tablets.

Table 5 .
Results of pharmacopeial test of chlorpropamide tablets.