Evaluation of formulation and processing factors on the disintegration and dissolution of immediate release tablets in fed state : formulation strategy towards minimizing viscosity mediated negative food effect
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Abstract
Bioavailability of tablets, particularly those containing BCS class III compounds, is generally reduced when administered with food. Delayed disintegration and dissolution of tablets in fed state is believed to be a reason for the impaired bioavailability. In addition to various physicochemical factors, food induced viscosity is one of the important factors in this regard. Formulations need to be optimized in view of this postprandial viscosity. Unfortunately, there exists a knowledge gap about the effect of food induced viscosity on formulation and process variables. In order to enhance the current understanding about the behavior of various excipients under fed conditions, 4 fillers with different functionalities i.e, Lactose(soluble), Dibasic calcium phosphate (DCP)(insoluble and non swellable), Microcrystalline cellulose (MCC)(insoluble but swellable) and Calcium carbonate (give effervescence in gastric medium); 3 disintegrants, i.e, Croscarmellose sodium (CCS)(swelling and wicking), Crospovidone (CPD)(shape recovery) and Sodium starch glycolate (SSG)(swelling); 3 lubricants i.e, Magnesium stearate (insoluble), Talc (insoluble) and Polyethylene glycol 6000 (soluble) and compressional force as a processing factor were assessed at different levels. Statistical evaluation of disintegration and dissolution times, in simulated fed and fasted state through D-optimal design, generated through MODDE 9.0 software, revealed the insignificance of lubricants and calcium carbonate in fed state. However, all disintegrants and fillers except calcium carbonate, showed significant effect on the disintegration and dissolution times, at different pH levels. To obtain a better insight, three independent studies, based on a single filler were designed, with an objective to study the use of three disintegrants i.e, CCS, CPD and SSG, alone and different levels of their combination at varying compressional force. In addition to the compendial tests of disintegration and dissolution, disintegration force development was also measured. In the presence of lactose as a filler, formulations containing CPD gave the shortest disintegration and mean dissolution times in fed state. However, these formulations were affected by the changes in compressional force. CCS containing formulations gave slightly higher disintegration and dissolution times, but were not affected by the changes in compressional force. In case of disintegrant combinations, a striking difference between the results of fed and fasted states was observed. Rapid disintegration and dissolution of drug was seen in fasted state, when higher levels of disintegrant combinations were used, while it was achieved in fed state when disintegrant combinations were used in low levels. Combination of CPD+CCS, was more effective among all combinations at either level and compressional force. In the presence of DCP as a filler, compressional force was significant in improving the drug release. Though slower than the lactose based formulations, CPD containing DCP based formulations improved the drug release in fed state, however the disintegration and dissolution was comparatively faster when evaluated in fasted state. In fed state, decreased levels of disintegrant combinations and increased compressional force were found to improve the disintegration and dissolution. While in fasted state, the effect of level of disintegrant combination was dependent on the compressional force i.e, at low compressional force drug release increased with a reduction in level of disintegrant combination. Combination of CPD+CCS in low levels was effective under higher compressional force. In the presence of MCC as a filler, disintegration times exceeded the compendial limits and drug release was impaired in fed state. However, CCS containing formulations gave better rate of drug release. Formulation containing combination of CCS+CPD at 2% each and compressed at 10 KN is interesting from a formulator’s perspective. Differences in the results obtained in fasted and fed states advocates the development of a standardized protocol to test the formulations in fed state during development phase. Concerned formulators and regulatory authorities may consider our work. Relatively rapid disintegration and dissolution times were observed with lactose based formulations. Similarly, CPD, CCS and their combinations were found to be effective in fed state. Therefore, formulators can optimize the proportion of CPD and CCS either alone or in combination with respect to the dose and nature of API used, in formulations, which are affected by the presence of food. As an extension of this work, we suggest to study the potential of combination of fillers with lactose. An optimum combination of fillers could be beneficial in reducing the disintegration time as well as the surrounding boundary layer around the tablets in fed state thereby enriching the formulation strategy towards minimizing the negative food effect.