(T1330-01-05) Augmenting In Vitro Dissolution of a Poorly Soluble API with a Multifunctional Lipidic Surfactant in an Orally Disintegrating Tablet

Purpose: Poor aqueous solubility resulting in low bioavailability and sub-optimal drug delivery remains a formidable challenge for BCS class II drugs¹. Surface-active solubilizers such as Acconon^® are multifunctional, non-ionic excipients with the ability to improve aqueous solubility of such actives. They act by facilitating the formation of solubilized phases yielding a solid solution from which absorption may occur in a pH-independent manner². Their use in tableting remains underexplored owing to their sticky nature. The present work explores the tableting potential of Acconon^® through a liqui-solid technology and aims to investigate the potential in vitro dissolution enhancement of a model BCS class II active, Loratadine (LOR), in an orally disintegrating tablet (ODT).

Methods: The study was executed in two different parts. PART A: Screening and optimization of surfactant and adsorbent: For solubility improvement of LOR, various ratios such as 1:0.5, 1:1 and 1:2 of LOR: lipidic surfactant (Acconon^® C-44 and Acconon^® C- 50) were evaluated. Different adsorbents like Zeopharm^® 250, Zeopharm^® 600, Aeroperl^® 300 Pharma and Tricafos^® 500 were assessed for conversion into free-flowing powder. The melt dispersions were prepared by melting surfactants at 65-75ºC and incorporating LOR into the molten lipids. They were then converted into free-flowing powder by using different adsorbents and the quantity of adsorbents required was noted. These mixtures were subjected to in vitro dissolution study in a discriminatory dissolution medium (pH 3.0) and percent drug release was noted at 5, 15 and 30 mins. PART B: Formulation of an ODT: The surfactant and adsorbent selected from the above study were used to formulate an ODT. The formula was optimized using different grades of lactose monohydrate and disintegrant to achieve a disintegration time (DT) of less than 30 secs. The blend for compression was prepared by mixing free-flowing powder of LOR, surfactant and adsorbent with particle engineered lactose monohydrate (SuperTab^® 50 ODT), crospovidone (Kollicon^® CL-SF), Acesulfame potassium (Sunett^® Pharma type D), Aerosil^® 200 Pharma, Orange flavor, bitter masker and magnesium stearate. The blend was prepared in a double cone blender at 15 rpm resulting from10 mins of blending and 3 mins of lubrication. The lubricated blend was compressed using a 6mm punch and further characterized for average weight, hardness, thickness, disintegration time, friability and multi-media dissolution (pH 1.2, 3.0, 4.5 & 6.8).

Results: Poorly soluble plain LOR displayed only 28.7% release in 30 mins, while the melt dispersions with Acconon^® C-44 and Acconon^® C-50 demonstrated significantly improved dissolution, resulting in ~100% and ~93% LOR release respectively in 30 minutes. The D₅ values steadily increased for Acconon^® C-44 (55.5% to 100%) with the highest %release being obtained for the 1:2 ratio of LOR: Acconon^®. Also, Acconon^® C-44 demonstrated ~2 fold improved dissolution of LOR as compared to Acconon^® C-50 in 5 mins at 1:0.5 and 1:2 ratios and was thus incorporated in the final ODT. Further, it was observed that all the adsorbents screened were able to convert molten drug: surfactant combination into free-flowing powder and their required concentration was noted to be in the order of Zeopharm^® 600 < Zeopharm^® 250 < Aeroperl^® 300 Pharma, Tricafos^® 500. Zeopharm^® 600 was thus chosen to be incorporated as an adsorbent in the ODT. The disintegration test of the optimized ODT formulation revealed that particle-engineered SuperTab^® 50 ODT along with Kollidon^® CL-SF was more suitable to achieve the desired DT of less than 30 sec. The concentration of sweetener and flavor was carefully optimized to improve palatability of ODT. The optimized batch could successfully be scaled up to 15, 000 tablets (n=2).  The multimedia dissolution profiles of LOR tablets exhibited no significant differences in D₁₅ values thus indicative of the pH independent nature of LOR release. The in vitro dissolution in terms of D₅ values of LOR tablets (~89%) at pH 3.0 was also found to be ~7 fold higher than marketed LOR IR tablets (~12%).

Conclusion: The present work clearly demonstrates the solubility enhancement potential of a multifunctional non-ionic lipidic surfactant like Acconon^® C-44. Adsorbents like Zeopharm^® 600 can be very useful for the conversion of liquid / pasty mass into free-flowing powders owing to their high specific surface area. The choice of particle engineered lactose governs the DT of an ODT containing a lipidic surfactant in the present study. The current work thus helps breach solubility barriers and lays the foundation for using lipidic surfactants in an ODT with the selection of lactose-disintegrant combination playing a critical role in defining its disintegration time.

References: 1. Insoluble drug delivery strategies: review of recent advances and business prospects, Sandeep Kalepu, Vijaykumar Nekkanti, Acta Pharmaceutica Sinica B 2015;5(5):442–453
2. Oral lipid-based drug delivery systems – an overview, Sandeep Kalepu & et al, Acta Pharmaceutica Sinica B 2013;3(6):361–372

Effect of concentration of lipidic surfactants on release of LOR at pH 3.0



Comparative Dissolution of LOR at pH 3.0



Multimedia dissolution of optimized batch