Background: The better control of the drug release with immediate effect is the major
concern to achieve better therapeutic action and patient compliance. The failure of the solid dispersion
complex during storage as well as in-vivo is another concern for the oral solid dosage form.
Objective: The prime objective of the present study was to optimize the biphasic minitablet incorporating
quality by design approach using the combination of waxy erodible and water-impermeable
excipients. Exploration of Soluplus as a precipitation inhibitor and Dexolve as a solubility enhancer
in oral solid dosage form was the secondary objective.
Methods: The drug-Excipient compatibility study was assessed by FTIR. Clozapine was chosen as
a model drug that has poor aqueous solubility. The complex was formulated using B-cyclodextrin
or HP B-CD or Dexolve by kneading method. The screening of solubility enhancers and their
amount were performed based on phase solubility study. The precipitation inhibitor was screened
as per the parachute effect study. Immediate release minitablets were formulated using a direct
compression method using different disintegrating agents. The IR minitablets were evaluated for
different evaluation parameters. The sustained release minitablets were formulated by hot-melt
granulation technique incorporating the Precirol ATO 5 as a waxy excipient and ethyl cellulose as
water impermeable excipient. The SR minitablet was optimized using a central composite design.
The amount of Precirol ATO 5 and ethyl cellulose were chosen as independent variables and %
drug release at 1, 6, and 10 h was selected as responses. The designed batches were evaluated for
different pre and post-compressional parameters. The IR and SR minitablets were filled in a capsule
as per dose requirement and evaluated for in-vitro drug release. The in-vivo plasma concentration
was predicted using the Back calculation of the Wagner - Nelson approach.
Results: Drug - Excipient study revealed that no significant interaction was observed. Dexolve was
screened as a solubility enhancer for the improvement of the solubility of clozapine. The Soluplus
was chosen as a precipitation inhibitor from the parachute effect study. The immediate-release
tablet was formulated using Prosolv EASYtab SP which yielded less disintegration time with better
flowability. The sustained release mini-tablet was formulated using Precirol ATO 5 and ethyl cellulose.
Two-dimensional and three-dimensional plots revealed significant effect of the amount of Precirol
ATO 5 and ethyl cellulose. The overlay plot locates the optimized region. The in-vitro drug release
study revealed the desired drug release of the final combined formulation. The in-vivo plasma
concentration-time confirms the drug release up to 12h.
Conclusion: The biphasic mini-tablets were formulated successfully for better control of drug release
leads to high patient compliance. The use of soluplus as a precipitation inhibitor is explored
in the oral solid dosage form for a poorly aqueous drug. Prosolv EASYtab SP was incorporated in
the formulation as super disintegrant. The amount of Precirol ATO 5 and ethyl cellulose significantly
affected drug release in sustained-release minitablet. The approach can be useful in the industry.