Liquisolid tablets – A rationale for formulation and process design

A significant proportion of new API’s in development are poorly soluble and require alternative formulation approaches to achieve adequate oral bioavailability. One option is to develop lipid-based formulations. Lipid formulations are typically liquids but can be converted into solid dosage forms via adsorption onto solid porous carriers. The term liquisolid describes a formulation which has been modified from a liquid to a solid for delivery as either a capsule or tablet dosage form. The aim of these studies was to investigate the compression properties of lipid-based liquisolid tablet formulations. The purpose was to establish a rationale and framework that could be used by a formulator when embarking on the development of a liquisolid formulation. The studies aimed to evaluate a range of lipid-based formulations loaded onto a selected adsorbent.

The optimal sorbent on to which lipid formulations were loaded was selected through screening studies. A Type I lipid formulation (Labrafac Lipophile WL1349®) was loaded onto selected sorbents, physical and compression characteristics were determined. The magnesium aluminometasilicates (Neusilin® grades) were the only sorbents to exhibit suitable compression properties with relatively low strain rate sensitivity values (< 3 %). The sorbent of choice (selected on compression characteristics) was determined to be Neusilin® US2. Further studies evaluated a model Type III (lipid formulation) SMEDDS preconcentrate (SPc) formulation, containing Labrafac Lipophile WL1349®. Neusilin® US2 was loaded at 50 %, 70 % and 90 % relative to the dry adsorbent. The compressibility of the Neusilin® US2 was reduced with increased SPc loading. The tablets produced from the SPc loaded Neusilin® US2 granules (without additional compression aids), were not suitably robust (relatively low tensile strength, low friability and extended disintegration). The compression range over which viable tablets were formed was limited for all granules at each loading level. For all granules, a critical force was reached at which the liquid phase appeared to dominate, and tablet tensile strength was reduced with increased force. This finding does not comply with general rules for powder compression.

Rather than a ‘yield point’ at which certain materials permanently deform; the granules appeared to reach a ‘liquid point’ at which the liquid dominated the tablet characteristics with increasing force/pressure applied. The addition of the ‘extra-granular’ excipients improved tablet robustness (tensile strength and disintegration), however friability was not improved at higher SPc loading levels as many tablets were found to cap/laminate during testing. To investigate the cause of variable tablet friability, Raman spectroscopy was used to analyse loaded granules and tablets. Dipyridamole was included as a model API in the SPc formulation (DSPc), at a relatively low concentration, which allowed a qualitative assessment of dipyridamole distribution within the loaded granules and tablets. Characterisation of both the granules and tablets showed poor dipyridamole homogeneity, with ‘pockets’ of high concentration. The size distribution of the pockets was similar irrespective of loading level. However, the quantity of pockets increased proportionally with DSPc loading. These observations suggest that the loaded granules prior to compression were inhomogeneous and of variable density and that the loading process required refinement.

This inhomogeneity may be a contributory factor to tablet friability. Alternative Type IV lipid formulations consisting of semi-solid excipients, Gelucire®44/14 and Vitamin E TPGS with the inclusion of dipyridamole were evaluated to determine if such excipients could infer improved tablet characteristics compared to Type I and III liquid formulations. The studies showed that the semi-solid materials Gelucire®44/14 and Vitamin E TPGS when loaded on Neusilin® US2 at loading levels of up to 90 % (relative to adsorbent weight) produced tablets > 1 MPa tensile with low friability (< 0.4 %) and rapidly disintegrated (< 10 min). The tablet formulations did not require the addition of extra granular compression aids, only 5 % w/w super-disintegrant (croscarmellose Na) and 1 % w/w lubricant (sodium stearyl fumarate) were necessary. In vitro dissolution testing was performed upon the various D-GEL and D-TPGS tablet formulations. The data showed that the D-GEL formulations achieved complete release of the API irrespective of loading level with 30 min.

However, for the D-TPGS formulations exhibited a retarded release in comparison, 90 % loaded tablets compressed at 10 kN failed to release the full extent of API under the test conditions. As a result of these studies a novel investigational plan has been proposed for the development of liquisolid tablet formulations, to aid a formulator when embarking on such a development exercise, highlighting considerations against which formulations could be designed and characterised. A number of characteristics are advised to be determined, which have been detailed as the ‘liquid points’. The understanding of these ‘liquid points’ is critical as it is these values for compression force/pressure and solid fraction that indicate the point at which the ‘liquid phase’ predominates the compression process and is likely to limit tablet robustness. These values therefore drive compression parameters and guide product scale-up. Continue the Thesis here