(T1230-03-18) Application of Hot Melt Extrusion Technology for the Preparation of Carbamazepine Extended-Release Tablets

Purpose: The present study was designed to develop carbamazepine extended-release tablets with acrylic acid-based polymer (Eudragit RLPO) using a continuous manufacturing process (melt granulation) and to match the USP dissolution test specification. Carbamazepine is an anti-convulsant and specific analgesic for trigeminal neuralgia that reduces polysynaptic responses and blocks post titanic potentiation. Carbamazepine is effective in partial and generalized convulsions and in mixed types. It is not effective in petit mal seizures. It reduces (or) abolishes pain in trigeminal neuralgia and glossopharyngeal neuralgia. Carbamazepine extended-release tablets are used to treat episodes of mania (or) mixed episodes i.e., symptoms of mania and depression that happen at the same time, in patients with bipolar disorder. It works by reducing abnormal excitement in the brain [1]. Hot-melt extrusion technology is an increasingly attractive process for the manufacture of various drug delivery systems. The drug is embedded in the carrier matrices as a solid dispersion/solution may allow for sustained or controlled release applications and dissolution rate improvement. Moreover, improved bioavailability has been achieved which demonstrates the value of HME as a powerful drug delivery tool [2].

Methods: Differential scanning calorimetry (DSC) was used in order to evaluate the glass transition temperature (Tg) and the melting temperature (Tm) of both the drug and the polymeric carrier. Extrusion was carried out using a 6 mm (minilab) extruder (Thermo Fisher Scientific, MA, USA). The filaments obtained from HME were granulated using a motor and pestle and then passed through a 30-mesh sieve to obtain the uniform size granules. A single tablet press was used to compress tablets with a dose of 100 mg by direct compression method. Different formulation compositions have been developed as shown in Table 1, and their rates of dissolution were compared. A USP dissolving type-II paddle with a sinkers system (Teledyne Hanson, Elite 8, Chatsworth, CA 31311 USA) was utilized to conduct an in-vitro drug release study. 900 ml of water was employed as the dissolving media, and the paddle speed was adjusted to 100 rpm. Examining samples for carbamazepine using the UV-Visible spectrophotometry at λmax 284.

Results: In the initial trials, different ratios of Eudragit RLPO were tried and the F3 formulation showed a favorable release profile compared to other formulations. However, it failed to meet the release requirements at the initial time points specified in USP. Different disintegrants were screened and sodium starch glycolate was selected and developed a few formulations by varying disintegrant concentrations. F7 met the required USP dissolution test specification with 6% disintegrant and 15% Eudragit RLPO with 50% drug load. A comparative study was performed between F7 tablets prepared using HME and the physical mixture of the same formulation (F7PM). Figure 1 displays the drug release behavior for each formulation. The dissolution parameters of F7 were calculated and compared with USP dissolution test specifications intended to achieve (Figure 1). To determine whether the drug had become amorphous, a DSC analysis was conducted, and the DSC thermograms were shown in Figure 2.

Conclusion: From the in-vitro dissolution studies, the tablets prepared from the F7 formulation containing 6% sodium starch glycolate and 15% Eudragit RLPO were meeting the requirements of the USP dissolution test specifications. The active polymorph present in the drug was converted to an amorphous state, observed from the DSC thermograms. In conclusion, preparing extended-release tablets through hot melt extrusion (HME) has significant value as a continuous manufacturing process.

References: 1. Gonzalez FJ, Robert H. Drug Metabolism, In Laurence Brunton, John Lazo, Keith Parker (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.), 2006.
2. Repka, Michael A et al. “Applications of hot-melt extrusion for drug delivery.” Expert opinion on drug delivery vol. 5,12 (2008): 1357-76. doi:10.1517/17425240802583421

Table 1: Composition of Formulations

Figure 1: In-vitro dissolution studies and Comparison of dissolution parameters of Formulation F7 with the USP standards

Figure 2: DSC thermograms of Carbamazepine, Eudragit RLPO, F7 HME blend, and F7 physical mixture