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Raghunadha Gupta1, Chitra Sundararajan1, Thomas Pauly2, Fred Monsuur2* 1 Alexandria Knowledge Park, Shameerpet, Hyderabad, India; 2 In der Hollerhecke 1, 67547 Worms, Germany; *corresponding author email: [email protected] synthesis intermediates purification technologies formulation excipients Evaluation of Porous and Non-Porous Solid Carriers for Lipid-Based Drug Delivery Systems Introduction: Liquid formulations pose several problems in terms of stability, handling, ease of use, etc. Solid dosage forms (tablets and capsules) are the most preferred formulations, as they offer the benefits of stability and robustness to the dosage form, as well as ease of administration, production, and packaging. Novel techniques such as liquisolid systems can enable the benefits of solid dosage forms by converting oil- and liquid-based formulations into stable, solid powders suitable for tabletting or capsule filling. + The liquisolid powder forms are typically obtained by adsorbing a liquid or oil onto a suitable solid carrier. Choice of the solid carrier is a critical factor for a successful liquid to solid conversion. An ideal solid carrier will adsorb large amounts of liquids while providing optimum density and free flowing behavior that can be easily processed further [1,2]. In addition, the carrier should also demonstrate excellent release properties. Here we present a comparison of liquid adsorption capacities of various fine powder solid carriers. This work compares synthetic porous silica carriers with aluminum silicates, sugars, cellulose and calcium phosphate. A new optimized, large particle, mesoporous silica gel referred to in this work as Syloid® XDP was found to be an excellent carrier choice for converting oily drug solutions into free flowing powders. The highly porous Syloid® XDP silica consistently out-performed other commercially available synthetic silicas made from precipitation and fumed processes for liquid adsorption. Results and Discussion: External Surface Area Oils are retained in the internal pore structure = Internal Porosity Table 4. Adsorption Capacities (g/100g of Solid Carrier) for Various Water Insoluble Excipients - Co-Solvents and Surfactants The scope of this work is to evaluate the behavior of Syloid® XDP silica as carrier for adsorption of various solubilizing excipients, in comparison with various other solid carriers. In this study, we present the results from a comprehensive evaluation of several well known solid carriers and their oil adsorption capacities. A wide selection of commonly used solubilizing agents - oils, lipids and surfactants were tested. This work is presented in the following categories: A.Evaluation of oil adsorption capacities of Syloid® 244 FP and New Syloid® XDP Silicas 1 and 2 and various other solid carriers - both silica-based and non-silica based carriers B.The five carriers with highest adsorption capacities - Syloid® 244 FP silica, New Syloid® XDP Silicas 1 and 2, Magnesium Aluminum Silicate (MAS) and Granulated Fumed Silica (GFS), were then evaluated with various oils, carriers and surfactants that are commonly used in lipid based formulations C.Free-flow behavior of these oil-loaded carriers were tested to determine the best carrier. D.Volume tests were performed with these oil-loaded carriers to determine capsule filling effectiveness E.Release of oil from the carriers was also evaluated. Name of Co-Solvent/Surfactant Syloid® 244 FP Silica Captex 355 355 Labrafac PG 344 Capmul MCM 343 Transcutol HP 345 Solutol HS 15 360 Cremophor EL 368 Labrasol 372 Labrafil M 1944 CS 339 Caprylol 90 344 Syloid® XDP Silica 1 296 287 285 306 312 317 324 292 296 Syloid® XDP Silica 2 296 291 288 310 318 323 324 292 296 MAS 338 331 333 340 322 363 372 321 335 GFS 282 262 283 276 306 309 297 269 268 C. Flow behavior of Oil-Loaded Carriers A crucial parameter for a solid carrier is the ability to provide a dry, free-flowing, and easily compressible powder after adsorption of large volume of liquid. The flow behavior of the oil-loaded powder is determined by the angle of repose test. A free-flowing blend should ideally have an angle of repose less than 40 degrees. The results are provided in detail in the following sections. A. Evaluation of Oil Adsorption Capacities of Syloid® XDP Silica with Various Other Solid Carriers. Commonly used solid carriers include excipients such as silica gel, fumed silicas, precipitated silicas, magnesium aluminium silicates, Microcrystalline cellulose (MCC), Talc, etc. The solid carriers are characterized by their ability to adsorb large volumes of liquids and provide a stable, solid, powder formulation which can then be processed with other suitable excipients (binders, disintegrants, etc.) and prepared into tablets and/or capsules. Carriers with high porosity and large surface area, such as porous silica, are therefore ideal choices. The angle of repose test was performed on oil-loaded Syloid® 244 FP and Syloid® XDP 1 silicas, Magnesium Aluminum Silicate, and Granulated Fumed Silica, at different adsorption ratios. Following oil loading at a ratio of 1:1.5 (carrier:oil) Syloid® FP and Syloid® XDP silicas resulted in dry and free-flowing powders, with Syloid® 244 FP and Syloid® XDP silicas having a lower angle of repose. Chart 4. Flow Behavior of Solid Carriers Loaded with Cremophor EL These solid carriers can be broadly grouped into: (i) Silica-based carriers - silica gel (Syloid® 244 FP and Syloid® XDP silicas), granulated fumed silicas, precipitated silicas, magnesium aluminum silicates, sodium magnesium aluminium silicates (ii)Non-silica based carriers - Microcrystalline cellulose, Talc, Di-Calcium Phosphate Anhydrous (DCPA), Sugars (Isomaltose) Silica-based carriers are popular choices, as they are non-toxic, non-reactive, and offer higher loading and stability due to their porous structure and large surface areas. Here, we tested the more commonly used carriers available today for oil adsorption including newly developed Syloid® XDP silica. The adsorption capacities were determined by mixing the oil into the carrier until a thick paste-like mass was obtained without any excess oil. The adsorption capacity is represented as (g/100g of solid carrier), which refers to the amount of oil (grams) adsorbed by 100 grams of solid carrier. Representative examples of the different classes of solubilizing excipients were used in this study. Chart 1. Chart 2. D. Volume Comparisons of Oil-Loaded Carriers One of the important applications of oil-loaded carriers is for the filling of capsules. Densities and volumes of the oil-loaded powders are therefore important to estimate amount of powder that can be used for filling the capsules. The four different carriers were loaded with oils at 1:1.5 ratio, and then the volumes were determined and compared with the initial volumes without oil loading. Syloid® 244 FP silica shows a significant decrease in volume (increase in density) after oil-loading. The new Syloid® XDP silica displays the lowest oil-loaded volume among all the carriers. Chart 5. Volume Change and Capsule Filling of Solid Carriers Loaded with Cremophor EL 2. Adsorption Capacities (g/100g of solid carrier) of Various Non-Silica Based Solid Carriers Dicalcium phosphate, talc, MCC and sugar based carriers are also used occasionally, but they show significantly lower adsorption capacities than the silica-based carriers. Chart 3. Adsorption Capacities (g/100g of solid carrier) for Cremophor EL E. Release of Oils from Oil-Loaded Carriers Among all the solid carriers, the silica based carriers show significantly higher oil adsorption capacities. The four best performing carriers were found to be Syloid® 244FP silica, Syloid® XDP silica, Magnesium Aluminum Silicate, and Granulated Fumed Silica. These four carriers were further evaluated for their adsorption of different types of solubilizing agents. An essential parameter of an ideal carrier is the ability to release the oils or oily APIs quickly and effectively. Here we tested Syloid® XDP Silica, Granulated Fumed Silica and Magnesium Aluminum Silicate for their oil-release behavior. Sesame seed oil and Miglyol® 812 oil were loaded on the carriers at a ratio of 1:1 (oil:carrier). The loaded carriers were then subjected to agitation with sufficient amount of water, followed by centrifugation. The separated oil and water layers were removed and amount of isolated oil was determined. It was observed that new Syloid® XDP porous silica, exhibited the best release properties, closely followed by Granulated Fumed Silica. Magnesium Aluminum Silicate showed the least efficient release of oil. B. Adsorption Capacities for Different Solubilizing Excipients Excipients used for solubilizing and stabilizing poorly soluble drugs include oils, lipids, organic solvents and surfactants. A few examples from these different classes of solubilizing excipients were used in this study to evaluate the adsorption capacities of silica and other solid carriers. Syloid® FP silica consistently shows the highest adsorption capacity among the different solid carriers, regardless of the nature of the solubilizing excipient. granulated fumed silica shows the lowest adsorption capacity, and the poorest flowability at higher loading. Table 3. Adsorption Capacities (g/100g of Solid Carrier) for Various Water Insoluble Excipients - Oils and Lipids Name of Oil Linseed oil Eucalyptus oil Lemon grass oil Peppermint oil Castor oil Sesame oil Olive oil Clove oil Oleic acid Tocopherol Syloid® 244 FP Silica 334 368 327 347 356 338 345 430 340 332 Syloid® XDP Silica 1 294 291 296 285 326 299 290 373 290 294 Syloid® XDP Silica 2 288 291 296 289 326 299 299 375 290 294 MAS 330 324 322 320 345 336 345 391 335 308 GFS 295 288 295 271 273 277 266 360 269 266 Conclusions Porous silicas offer excellent properties as a solid carrier for various liquid formulations, due to their ideal combination of porosity, surface area, particle size, and morphology. Porous silicas also demonstrate high adsorption capacity with several oils and lipophilic agents that are commonly used for stabilizing and loading and maintain good flowability of the resulting powders. The solid hydrophilic carrier Syloid® XDP silica demonstrate the best overall properties for oil loading, flowability, consistent volume after loading, high bulk density and maximum filling amount for capsules, as well as the best release properties. This combination of properties make it the ideal carrier for use in various techniques such as solid dispersion, self-emulsifying drug delivery systems (SEDDS, SMEDDS, SNEDDS), and other-lipid based technologies. www.discoverysciences.com Testing Parameters Available Upon Request Acknowledgements: The authors would like to acknowledge Priyanka Reddy for her assistance in this work. References: [1] Javadzadeh, Y et al: Liquisolid technique as a Tool for the Enhancement of Poorly Water-Soluble Drugs and Evaluation of their Physiochemical Properties, Acta Pharm. 57 (2007) 99-109. [2] Satheeshbabu.N et al: Liquisolid: A Novel Technique To Enhance Bioavailability, Journal of Pharmacy Research 2011,4(1),181-185. GRACE®, Davisil®, and SYLOID® are trademarks, registered in the United States and/or other countries, of W. R. Grace & Co.-Conn. SYNTHETECHâ„¢ is a trademark of W. R. Grace & Co.-Conn. CREMOPHOR® and SOLUTOL® are registered trademarks of BASF. TRANSCUTOL®, LABRASOL®, LABRAFIL®, and CAPRYOL® are a registered trademarks of Gattefosse. This trademark list has been compiled using available published information as of the publication date of this presentation and may not accurately reflect current trademark ownership or status. Alltech Associates, Inc. is a wholly owned subsidiary of W. R. Grace & Co.-Conn. Grace Materials Technologies is a business segment of W. R. Grace & Co.-Conn., which now includes all product lines formerly sold under the Alltech and GRACE DAVISON brand. ©Copyright 2013 Alltech Associates, Inc. All rights reserved. PP259 JP