(T1130-01-05) Platform Technology for Introducing Liquid Solubilisers in Tablet Formulations

Purpose: Poorly soluble drugs need special consideration and strategies while designing their solid oral formulations since their rate of dissolution is an important factor which needs to be look upon to ascertain therapeutic efficacy. For BCS class II drugs, the dissolution process is the rate-controlling step, which determines the rate and degree of its absorption. To address this issue, a wide range of nonionic water-dispersible liquid surfactants are available that aid in solubilizing and thereby, increasing the oral bioavailability of poorly water-soluble drugs. However, owing to their liquid nature, formulators find it challenging to incorporate these solubilisers into solid oral formulations such as tablets & granules. Thus, the current study demonstrates an industrially feasible platform technology to incorporate a nonionic water-dispersible liquid surfactant in tablet formulation for poorly water-soluble drug. Ondansetron Hydrochloride Dihydrate (OHD) (dose 8 mg) is a sparingly water soluble selective 5-HT3 serotonin-receptor antagonist belonging to BCS Class 2 that requires an additional solubilizer to achieve the required dissolution profile. In the present case study, Labrasol^®ALF, a nonionic water-dispersible liquid surfactant, is used to solubilize and increase dissolution profile of OHD, for developing immediate release tablets of the latter. The devised technique of this study can serve as a platform technology to incorporate liquid solubilizers in oral solid dosage forms.

Methods: Solubility of OHD was determined in a wide range of solubilizers to select the most suitable for the Active Pharmaceutical Ingredient (API). For tablet formulation, OHD was dispersed in Labrasol^®ALF & was added to other intragranular ingredients in a rapid mixer granulator to conduct wet granulation. A combination of low density silicified microcrystalline cellulose, dicalcium phosphate & mannitol was used as a carrier system to adsorb & hold the drug in the tablet formulation in a dispersed form. Tablets were compressed on fully motorized multi-station tablet press using 5mm round standard concave punch. Further, the granule & tablet properties such as particle size distribution, granule flow properties, tablet hardness, disintegration time & friability were studied. The solid-state characteristics of the drug in the formulation were studied by Differential scanning calorimetry (DSC) from 30˚C to 200˚C and X-Ray Powder Diffraction (XPRD) to understand the crystalline or amorphous nature of the drug in the formulation vis-à-vis pure drug. The drug-excipient interactions were studied using Fourier Transform Infrared Spectroscopy (FTIR). The in vitro dissolution study was conducted as per USP Dissolution Test 5 as specified in monograph for OHD Tablets USP 33.

Results: Amongst the various solubilisers evaluated OHD showed greater solubility in Labrasol® ALF & hence this solubiliser was selected for the tablet formulation development. A combination of low density silicified microcrystalline cellulose, dicalcium phosphate & mannitol served as a good carrier base for adsorbing the drug dispersion in liquid solubilisers & afforded sturdy tablets with no oozing of liquid on the tablet surface. The granule and tablet properties were well-within the acceptable range to yield good tablets. The selected solubiliser was able to improve the dissolution rate & meet the test specifications as per Ondansetron immediate release tablets USP using this platform technology. Overall, this technique to incorporate liquid solubiliser in a solid dosage form was found to be easy, effective, and industrially scalable. It does not require any additional step or unit operation in the usual process for tablet production.

Conclusion: The developed platform technology demonstrated ease of manufacturing, versatility for wide range of API & industrial viability for incorporating solutions or dispersions of poorly water-soluble APIs in non – ionic lipid based liquid solubilisers. The improved dissolution behaviour of OHD tablets manufactured by this platform technology is attributed to the presence of the liquid solubilizer in close contact with the drug, resulting in increased wetting and surface area for dissolution.

References: Design and development of liquisolid compact of candesartan cilexetil to enhance dissolution; S. Tulsankar, et.al., Journal of Pharmacy Research, 7(2013) 381 – 388.

Acknowledgements: The authors would like to acknowledge BASF (India) for helping with gift samples of Kollidon® 30 polymer.

Figure 1. Schematic representation of manufacturing process

Figure 2. In Vitro Dissolution Profile of the Ondansetron IR Tablets USP