synthesis intermediates

purification technologies

formulation excipients

Evaluation of Porous and Non-Porous Solid Carriers for Lipid-Based Drug Delivery Systems

Raghunadha Gupta1, Chitra Sundararajan1, Thomas Pauly2, Fred Monsuur2*1Alexandria Knowledge Park, Shameerpet, Hyderabad, India; 2In der Hollerhecke 1, 67547 Worms, Germany; *corresponding author email: Fred.Monsuur@grace.com

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.

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.

Chart 2. Chart 1.

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. SYNTHETECH™ 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.

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Results and Discussion:

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.Thefivecarrierswithhighestadsorptioncapacities-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-flowbehavioroftheseoil-loadedcarriersweretestedtodeterminethebestcarrier.D.Volumetestswereperformedwiththeseoil-loadedcarrierstodeterminecapsulefillingeffectivenessE. Release of oil from the carriers was also evaluated.

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.

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.

Internal Porosity

External Surface Area

Oils are retained in the internal pore structure

+ =

PP259 JP

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

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.

Name of Oil Syloid® 244 FP Silica Syloid® XDP Silica 1 Syloid® XDP Silica 2 MAS GFSLinseed oil 334 294 288 330 295Eucalyptus oil 368 291 291 324 288Lemon grass oil 327 296 296 322 295Peppermint oil 347 285 289 320 271Castor oil 356 326 326 345 273Sesame oil 338 299 299 336 277Olive oil 345 290 299 345 266Clove oil 430 373 375 391 360Oleic acid 340 290 290 335 269Tocopherol 332 294 294 308 266

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

Table 3. Adsorption Capacities (g/100g of Solid Carrier) for Various Water Insoluble Excipients - Oils and Lipids

E. Release of Oils from Oil-Loaded Carriers

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.

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.

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 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

Name of Co-Solvent/Surfactant Syloid® 244 FP Silica Syloid® XDP Silica 1 Syloid® XDP Silica 2 MAS GFSCaptex 355 355 296 296 338 282Labrafac PG 344 287 291 331 262Capmul MCM 343 285 288 333 283Transcutol HP 345 306 310 340 276Solutol HS 15 360 312 318 322 306Cremophor EL 368 317 323 363 309Labrasol 372 324 324 372 297Labrafil M 1944 CS 339 292 292 321 269Caprylol 90 344 296 296 335 268

Table 4. Adsorption Capacities (g/100g of Solid Carrier) for Various Water Insoluble Excipients - Co-Solvents and Surfactants

0

50

100

150

200

250

300

350

400

Syloid® 244 FP Silica

Syloid® XDPSilica 1

MAS GFS Precipitated Silica 1

Precipitated Silica 2

SAS

Ad

sorp

tio

n C

apac

itie

s (g

/100

g)

Adsorption Capacities for Linseed Oil

0

50

100

150

200

250

300

350

400

Syloid® 244 FP Silica

Syloid® XDPSilica 1

MAS GFS Precipitated Silica 1

Precipitated Silica 2

SAS

Ad

sorp

tio

n C

apac

itie

s (g

/100

g)

Adsorption Capacities for Cremophor EL

0

50

100

150

200

250

300

350

400

Syloid® 244FP Silica

Syloid® XDP Silica 1

Dicalcium Phosphate

MCC Talc Isomaltose

Ad

sorp

tio

n c

apac

itie

s (g

/100

g)

Adsorption Capacities for Cremophor EL

0 5

10 15 20 25 30 35 40 45 50

Syloid® 244 FP Silica

Syloid® XDP Silica 1

MAS GFS

An

gle

of

rep

ose

(d

egre

es)

Solid Carriers

Flow Properties of Oil-Loaded Carriers

Without loading Loaded 1:1.5

0

100

200

300

400

500

600

700

Syloid® XDPSilica 1

GFS MAS Syloid® 244 FP Silica

Maximum Filling Amount (mg) in Zero Size Capsules

Bu

lk D

ensi

ty in

g/L

, Max

Fill

Am

ou

nt

in m

g

Bulk density

Max. Filling Amt (mg of 1.5:1 load)

0

10

20

30

40

50

60

70

80

90

Syloid® XDPSilica 1

GFS MAS

% O

il R

elea

se

Carriers

Release of Oils from Carriers

Sesame seed oil

Miglyol® 812 oil

0

10

20

30

40

50

60

70

80

90

Vo

lum

e (m

L)

Solid Carriers

Volume Change of Cremophor Loaded (1:1.5) Solid Carriers

Solid volume without oil

Oil loaded solid volume

Syloid® 244FP Silica

Syloid® XDPSilica 1

GFS MAS