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:
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.
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.
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
Adsorption Capacities (g/100g)
Adsorption Capacities (g/100g)
350
300
250
200
150
100
50
0
Precipitated
Silica 1
GFS
282
262
283
276
306
309
297
269
268
Chart 4. Flow Behavior of Solid Carriers Loaded with Cremophor EL
Angle of repose (degrees)
Flow Properties of Oil-Loaded Carriers
50
45
40
35
30
25
20
15
10
5
0
Without loading
Loaded 1:1.5
Syloid® 244
FP Silica
Syloid® XDP
Silica 1
MAS
GFS
Adsorption Capacities for Cremophor EL
400
GFS
MAS
338
331
333
340
322
363
372
321
335
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 2.
Adsorption Capacities for Linseed Oil
Syloid® XDP Silica 2
296
291
288
310
318
323
324
292
296
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.
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.
Syloid® XDP Silica 1
296
287
285
306
312
317
324
292
296
C. Flow behavior of Oil-Loaded Carriers
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)
MAS
Internal
Porosity
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.
Syloid® XDP
Silica 1
=
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.
Syloid® 244
FP Silica
External
Surface
Area
Oils are retained
in the internal
pore structure
Precipitated
Silica 2
Solid Carriers
400
350
D. Volume Comparisons of Oil-Loaded Carriers
300
250
200
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.
150
100
50
0
Syloid® 244
FP Silica
SAS
Syloid® XDP
Silica 1
MAS
GFS
Precipitated
Silica 1
Precipitated
Silica 2
SAS
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.
Maximum Filling Amount (mg) in Zero Size Capsules
Volume Change of Cremophor Loaded (1:1.5) Solid Carriers
700
Bulk Density in g/L, Max Fill Amount in mg
90
80
70
Chart 3. Adsorption Capacities (g/100g of solid carrier) for Cremophor EL
Solid volume without oil
Volume (mL)
60
Adsorption capacities (g/100g)
Adsorption Capacities for Cremophor EL
400
350
Oil loaded solid volume
50
40
30
300
250
20
200
10
150
100
0
Syloid® 244
FP Silica
50
0
Syloid® 244
FP Silica
Syloid® XDP
Silica 1
Dicalcium
Phosphate
MCC
Talc
Syloid® XDP
Silica 1
Isomaltose
GFS
600
Bulk density
Max. Filling Amt
(mg of 1.5:1 load)
500
400
300
200
100
0
MAS
Syloid® XDP
Silica 1
GFS
MAS
Syloid® 244
FP Silica
Solid Carriers
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.
Release of Oils from Carriers
B. Adsorption Capacities for Different Solubilizing Excipients
% Oil Release
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
90
80
70
60
50
40
30
20
10
0
Sesame seed oil
Miglyol® 812 oil
Syloid® XDP
Silica 1
Conclusions
GFS
MAS
Carriers
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.
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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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