Development and evaluation of oral disintegrating tablets using different formulations and process variables

MastersOrally Disintegrating Tablets (ODTs) have become a very popular dosage form as they disintegrate rapidly (< one minute) in the mouth and don’t require water for administration. This is due to the increased patient compliance, pleasant mouth feel, ease of administration & swallowing and rapid disintegration and dissolution. There are three main manufacturing methods used for the production of ODTs, namely, freeze drying, molding and compression method. Also, different technologies are routinely used for manufacturing ODTs as Orasolv®, Durasolv®, WOWTAB®, Flashtab®, Zydis®, Quicksolv® and Lyoc® technologies. Some methods of manufacturing ODTs are complex, require multiple processes and don’t provide all ODTs ideal properties. For example, freeze drying and molding provide very light and porous products which disintegrate very rapidly, but they are expensive and produce fragile products. On the other hand, compression method is the easiest and cost effective method for the production of ODTs. It has several advantages as simple equipment, commonly available excipients, high doses can be used and limited number of manufacturing steps. The specific aim of this study was to develop a simple and inexpensive method of manufacturing ODTs and studying the effect of different formulation and process variables. Dextromethorphan hydrobromide (DM), a sparingly water soluble drug used in treatment of cough, was chosen as a model drug. ODTs formulations of DM have the advantages of both solid and liquid dosage forms and are useful for immediate relief of cough with improved patient compliance and to help patients of all age groups who have difficulty in swallowing. Orally disintegrating tablets containing 15 mg of DM were manufactured using direct compression method. Experiments were performed according full factorial designs to evaluate effects of formulation parameters like type & concentration of diluents, concentration of disintegrating agent and their interactions on dextromethorphan hydrobromide ODTs properties. Dextrates, microcrystalline cellulose and spray dried sorbitol were used as diluents of different properties, in addition to croscarmellose sodium (CCS), which was used as a superdisintegrant. It was found that microcrystalline cellulose at 30 % level in combination with croscarmellose sodium at 3 % level produced ODTs with the lowest disintegration time (12.5 sec. ± 1.22), low T50 (0.8 min.), the time required for 50 % of loaded drug to be released, and a high hardness (4.92 kp ± 0.28). Additionally, ODTs consisting of 30.6% of dextrates and 4.2% of croscarmellose sodium produced tablets with low disintegration time (21.5 ±1.37 sec), low T50 (0.87 min) and high hardness (3.99 ± 0.29). Moreover, sorbitol at 17.5 % levels in combination with croscarmellose sodium at 4.89 % levels produced ODTs having a low disintegration time (27.5 ± 1.6 sec), a lower T50 (1.5 min.) and hard tablets (4.36 ± 0.25 kp). Effect of different formulations (disintegrating agents and lubricants) and process variables (compression force) on the optimized formulation were evaluated. Crospovidone (CP) and sodium starch glycolate (SSG) were used as superdisintegrants at the same concentration of optimized croscarmellose concentration. Sodium stearyl fumarate, talc, stearic acid, sodium benzoate and glycerol dibehenate were used as lubricants at the same concentration of magnesium stearate (1%). In addition, different compression forces (2-7 kN) were used as a process variable. ODTs composed of microcrystalline cellulose at 30 % level in combination with croscarmellose sodium at 3 % level was chosen as optimized formula, as it showed the lowest disintegration time, low T50 and hard tablets amongst other tested ODTs formulations. Disintegration time of optimized tablets was not significantly affected by replacing CCS by crospovidone, but it was significantly (p-value < 0.05) increased from 12.5 sec. ± 1.22 to 15.5 ± 0.56 sec in tablets prepared by sodium starch glycolate. Furthermore, hardness of the manufactured tablets was not significantly affected by the use of crospovidone and sodium starch glycolate instead of CCS. Disintegration time and hardness of tablets was not significantly affected by the change of lubricant. However, dissolution rate was affected by changing lubricant type and it can be arranged as follows: glycerol dibehenate > Mg stearate > sodium stearyl fumarate. Disintegration time and hardness were significantly (p-value < 0.05) increased by increasing compression force from 2 kN to 7 kN. The optimized formula was compared to a ready ODTs system (PharmburstTM) and to marketed conventional tablet product (Tussilar®). The effect of storage under accelerated conditions (Temp: 40 ± 2 °C and relative humidity: 75 ± 5 %) and long term conditions (Temp: 25 ± 2 °C and relative humidity: 60 ± 5 %) were carried out for three months for some selected ODTs formulations. The obtained results revealed that disintegration time of the optimized ODTs formula (12.5 sec. ± 1.22 sec) was significantly (p-value < 0.05) lower than disintegration time of the Pharmburst TM formula (14.17 sec. ± 0.75 sec). However, PharmburstTM based formula gave a higher dissolution rate than the optimized one. On the other hand, hardness of both two formulas wasn’t significantly different. Also, it was found that optimized formula had significantly (p-value < 0.05) lower hardness and disintegration time with a higher dissolution rate than Tussilar® as well. Disintegration time of optimized formula was observed to be not significantly changed upon storage under long term and accelerated storage conditions up to three months. However, hardness was significantly (p-value < 0.05) decreased from 4.92 ± 0.28 kp to 2.37 ± 0.54 kp under accelerated conditions and was stable under long term conditions for three months. ODTs formulations composed of dextrates and sorbitol showed softening when stored under accelerated conditions. However, dextrates based formula was stable when stored under long term conditions. Furthermore, sorbitol based formula was significantly affected (p-value < 0.05) in regard to hardness (from 5.55 ± 0.32 kp to 2.87 kp) and disintegration time (from 49.33 ± 5.85 sec to 15.67 ± 1.96 sec). Additionally, the formula containing mannitol was stable only when stored in long term conditions but a significant increase (p value < 0.05) in hardness from 3.91 ± 0.32 kp to 5.58 ± 0.73 kp occurred when they were stored in accelerated conditions. Finally, it was concluded that dextromethorphan hydrobromide oral disintegrating tablets were developed using microcrystalline cellulose and croscarmellose sodium. These tablets provided low disintegration time, T50 and high hardness that are acceptable for ODTs