MEMPD157

pharma SOLUTIONS
Characterization of Newly Developed Micronized Poloxamers for Poorly Soluble Drugs

Anisul Quadir, Ph.D, MBA Releasing Technology Workshops Controlled Release Society Meeting Miami, June 19, 2005
n Actives n Excipients n Contract Manufacturing n Value Added
Helping make Pharmaceuticals betterTM
Poloxamers Chemical Nature
Poloxamers are block-copolymers consisting of Polyoxyethylene-(POE-) and Polyoxypropylene-(POP-) units Chemical composition: CH HO CH 2 CH 2 O a CH 2 CH 3 O b CH 2 CH 2 O a H
POE-unit
Pharmacopoeial name Poloxamer 188 Poloxamer 407 a = ca. 79 a = ca. 98
POP-unit
POE-unit
Trade Name
b = ca. 28 b = ca. 57
Lutrol F 68 Lutrol F 127
Actives
Excipients
Contract Manufacturing
Value Added
Lutrol F Grades
Brand Name n Lutrol F68NF n Lutrol F127NF
Pharmacopeial Name n Poloxamer 188 n Poloxamer 407
Also Available
n n n
Lutrol F87NF Lutrol L44NF Lutrol F108NF
n n n
Poloxamer 237 Poloxamer 124 Poloxamer 338
Actives
Excipients
Value Added
Poloxamers Characteristics
The character of each poloxamer in terms of:

n n n
molecular weight appearance hydrophilicity / hydrophobicity solubility
is determined by the chain length of the
polyoxyethylene(EO-) units
AND
n
polyoxypropylene(PO-) units
Actives
Excipients
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Poloxamer Grid
4000
401
402
403
407
Molecular weight of PO-part
3625 3250 2750 2250 2050 1800 1450 1200 950 0
Liquid
331 333
Paste
334 335
Solid
338
272
278
221
224
225
227
228
202
205
207
181
182
183
184
185
188
122 101
123
124 105 108
10
20
30
40
50
60
70
80
Percentage EO-part (%)

Poloxamer grades Definition of Number Code
Mw of PO-part EO-part (Wt.%) Poloxamer 18 8 Poloxamer 40 7 18 x 100 = 1800 40 x 100 = 4000 8 x = 7 x = 10 80 10 70
Actives
Excipients
Value Added
Lutrol Grid
12000 11000 10000
L121
L122
P123
F127
Liquid
L101 P103
Paste
P104 P105
Solid
F108
Molecular weight
9000 8000 7000 6000 5000 4000 3000 0

L31 L61 L81
L92
F98
P84
P85
F87
F88
L72
P75
F77
L62
L63
L64
P65
F68
L42
L43
L44 L35 F38
10
20
30
40
50
60
70
80
Percentage EO-part (%)

Lutrol F Grades Nomenclature
Mw Lutrol F 6 8 6 = x 1000 6000
EO-part (Wt.%) 8 x 10 = 80 7 x 10 = 70
Lutrol F 12 7
12 x 1000 = 12000
Actives
Excipients
Value Added
Lutrol F Grades Molecular Weight

arbitr. units 5 4,5 4 3,5 3 2,5 2 1, 1 0,5 0 lot-No. 89-0823 lot-No. 87-0807
100
1.000
molecular weight
10.000
100.000
Lutrol F 68 lot-No. 89-0823 lot-No. 87-0807

n
Mw 8,600 9,000
Actives n
Mn 7,600 8,100
Excipients n
(Mw/Mn) 1.4 1.4

Contract Manufacturing n Value Added
Lutrol F127 Molecular Weight

arbitr. units 5 4,5 4 3,5 3 2,5 2 1, 5 1 0,5 0
100
1.000
molecular weight
10.000
100.000
Lutrol F 127 lot-No. 41-0805 lot-No. 64-0806
Mw 13,400 13,500
Mn 9300 9500
(Mw/Mn) 1.4 1.4
Actives
Excipients
Value Added
Lutrol F127 Reason for Bimodal Distribution

n
The molecular weight distribution is dependant on side reactions, which occur during propylene oxide polymerization. During formation of POP block, a fraction of propylene oxide may be converted to allyl alcohol which will futher react with PO and EO producing a polymeric material about half the molecular weight of the main product. This segment constitute the unsaturation part of Lutrol F127 ( 0.048 meq/gm). In the USP, the average molecular weight is 9840 to 14600.
Actives
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Formation of Unsaturation
H H H
O
KOH
H H O
H
n+1
CH 2 CHO CH 3
n
Unsat. in USP/NF for 407 = 0.048 + 0.017 mEq/g
CH 2 CHO CH 3
CH 2 CH 2 O
Actives n Excipients CONFIDENTIAL
Value Added
Functionality of Poloxamer 407
CH3 HO-(CH2-CH2-O)x-(CH2-CH-O)y-(CH2-CH2-O)x-H where x = approx. 98 and y = approx. 57 Poloxamer is terminated with hydroxyl group therefore further reactions will not occur (will not self polymerize)
Principle of Micellization
surfactant m o lecule
Polar Solvent
Actives
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As a Solubilizer
Solubilization capacity of a poloxamer is believed to be dictated by the hydrophobic portion One theory is that in water, the poloxamer molecules arrange themselves in an umbrella like configuration:
POP Group
One Poloxamer molecule
POE Group
Actives
Excipients
Value Added
Limiting Aggregation Concentration
From the available literature: Poloxamer 188 (Lutrol F 68)

Poloxamer 338 (Lutrol F 108) Poloxamer 407 (Lutrol F 127)* 6.0 4.74 2-3 micromoles/ liter micromoles/ liter micromoles/liter
* Estimated, no published literature.
Actives
Excipients
Value Added
Lutrol F Grades Applications
Solubilizer Solubilizer
Gels Gels
Suspension Suspension Stabilizer Stabilizer
Melt //Spray Melt Spray Granulations Granulations
Actives
Excipients
Value Added
Lutrol F Grades (Poloxamers)
Prill
n n
Microprill
n n n
Lutrol F68 Prill Lutrol F127 Prill
Lutrol 68*micro Lutrol 127* micro Particle Size Range

n n
d (0.5) = 50micron d (0.9) = 90 micron
*Development Product
Actives
Excipients
Value Added
Advantages of Microprilling
n n n n n n n
Average particle size 50 micron Stronger solubilization activities Controlled dissolution rate Reduction of die-wall friction Achievement of homogeneous blend Elimination of dose dumping Effective water soluble lubricant
Actives
Excipients
Value Added
Microprill Lutrol Particle Size Specification
Microprill meets the following specification n Max. 10% retain in 106 micron (#140 Screen) n Max. 50% retain on 53 micron (#270 Screen)
n
Using Alpine Air Jet Sieve Analysis Chemical Specification is identical to regular prill and complies with USP/NF specification
Actives
Excipients
Value Added
SEM
Lutrol F68 Prill x50 magnification
Lutrol 68 Microprill x500 magnification
Actives
Excipients
Value Added
Particle Size Using Malvern Mastersizer 2000
Lutrol F68 Prill

Particle Size Distribution
13 12 11 10 9 Volume (%) 8 7 6 5 4 3 20 2 1 0 0.1 1 10 Particle Size (m) 100 1000 10 0 3000 60 50 40 30 100 90 80 70
Volume (%)
Lutrol 68 Microprill
Particle Size Distribution
10 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 0.1 100 90 80 70 60 50 40 30 20 10 1 10 Particle Size (m) 100 1000 0 3000
F68 Prill, sifted, WPOZ-551BK4 Averaged Result, 08/06/04 11:25:51
F68 microprilled, WPNZ-664BMP Averaged Result, 08/06/04 11:33:33
Actives
Excipients
Value Added
Surface Area
Sample
BET Surface (m2/g)
Lutrol F68 Lot # 55-0003 Lutrol 68 Microprill Lot # WPNZ-664BMP
Not Possible
0.18
Actives
Excipients
Value Added
Bulk / Tapped Density
Material Lutrol F68 Prill Lot # WPDX-577B Lutrol 68 Microprill Lot # WPNZ-664BMP
Bulk Density (g/cm3) 0.56
Tapped Density (g/cm3) 0.60
True Density (g/cm3) 0.99
0.52
0.78
1.10
Actives
Excipients
Value Added
Melt Viscosity
Viscosity (cps) Initial Stabilized
F68 Prill 807 783
68 Microprill 730 720
Equipment :
Brookfield RVT-DVII with Thermoseal & Temperature Controller Temperature Set and Maintained at 80C, Spindle #27
Actives
Excipients
Value Added
Molecular Weight Distribution (GPC)

-
Sample Name
Mn
Mw
MP
Polydispersity
% Area
Area
Retention Time
Project #
Lutrol F68 Microprill WPNZ-664BMP

(microprill) Date Acquired 10/18/04 9:05:37 AM
8611
9332
9956
1.083755
100.0
2861502
18.411
2S011
Lutrol F68 Prill WPOZ-551BK4

(normal prill) Date Acquired 10/18/04 10:45:31 AM
8809
9656
10288
1.096190
100.0
3711903
18.356
2S011
15.00
16.00
17.00
18.00
19.00
20.00
21.00
22.00 23.00 Minutes
24.00
25.00
26.00
27.00
28.00
29.00
30.00
Actives
Excipients
Value Added
Differential Scanning Calorimetric Data
Material Lutrol F68 Prill Lutrol 68 Microprill
To 48.9 50.1
Tp 51.6 52.4
H 121.7 121.7
To = Extrapoloated onset of melting endotherm in C Tp = Peak of melting endotherm in C H = Enthalpy of melting endotherm in joules/gram
Actives
Excipients
Value Added
DSC
Lutrol F68 Prill

Run : 2 2nd heat
DSC
Heat Flow (W/g)
50.09C 134.3J/g
-2
53.56C
-4
-6 -60
Exo Up
Lutrol 68 Microprill
-40 -20 0 20 40 60 80 100
Universal V3.8B TA Instruments
Temperature (C)
DSC
2
Heat Flow (W/g)
2nd heat
2C/min
49.64C 119.8J/g
-1
52.32C
Exo Up
-2 0
10
20
30
40
Temperature (C)
50
60
70
80
90
100
Actives
Excipients
Value Added
X-Ray Diffraction
14000
13000
12000
11000
n Lutrol F68 Prill n Lutrol 68 Microprill
10000
9000
Lin 8000 (Co unt 7000 s)

6000
5000
4000
3000
2000
1000
0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
2-Theta - Scale -2 - - - -.
Actives
Excipients
Value Added
pharma SOLUTIONS
Case Study Effects of micronized poloxamers on poorly water soluble drugs
Formulations
Material
Ibuprofen Carbamazepine Ltrol micro Di-calcium Phosphate Calcium Carbonate 90A Kollidon CL Aerosil 200 Magnesium Stearate
Formulation A (%) 5.0 5.0, 25.0, 50.0 79.0, 69.0, 59.0, 34.0 10.0 0.5 0.5
Formulation B (%) 5.0 25.0, 50.0 59.0, 34.0 10.0 0.5 0.5
Actives
Excipients
Value Added
Ibuprofen Capsule Data
Capsules containing Ibuprofen and Lutrol 127 Micro

90 80 70 60 50 40 30 20 1:10 Ratio 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Control 1:1 Ratio 1:5 Ratio
% Drug Release
Time (Hrs)
Dissolution Media pH 4.5 buffer
HPLC Column 5m C18 150mm x 39mm

n Actives n Excipients n
Mobile Phase: H20:Acetonitrile (40:60)

Ibuprofen Tablet Data
Tablets containing Ibuprofen and Lutrol 127 Micro

120
100
% Drug Release
80
60
40
1:1 Ratio 1:5 Ratio
20
1:10 Ratio Control
0 0 1 2 3 4 5
Time (hrs)


Ibuprofen and Lutrol F127 Prill vs. Micro grades (1:10)
Ibuprofen tablets containing Lutrol 127 Prill and Micro grades

120
100
% Drug Release
80
60
40
Lutrol 127 micro

20
Lutrol F127 Prill
0 0 1 2 3 4 5
Time (hrs)


Conclusion For Ibuprofen
The addition of Lutrol 127 micro improved the dissolution of Ibuprofen
Tablets showed a greater improvement in dissolution compared to capsules
The thermoreversible gelling effect, along with the smaller particle size of Lutrol 127 micro gave a controlled release profile
Actives
Excipients
Value Added
Carbamazepine Formulations Process
Dissolution studies with tablets via direct compression and solid dispersion were evaluated Regular prill used for Solid dispersion and Microprill for Direct Compression Tablets compressed using 9.5mm round flat face bevel edge tooling Target weight 400mg, target hardness 4-5Kp Using Carbamazepine as a model drug, due to its limited solubility in water dissolution studies were carried out using a co-solvent of water and ethanol (70:30)
Actives
Excipients
Value Added
Carbamazepine and Lutrol 127 1:5 ratio
Carbamazepine and Lutrol 127 micro 1:5 Ratio

90 80 70
% Drug Release
60 50 40 30 20 10
Direct Compression Solid Dispersion Control
0 0 1 2 3 4 5
Time (hrs)
Dissolution Media 70:30 Ethanol:Water
HPLC Column 5m CN 250mm x 4.6mm

Mobile Phase: H20:MeOH:THF (85:12:3)


90 80 70
% Drug Release
60 50 40 30 20 10 0 0 1 2 3 4 5
Solid Dispersion Direct Compression Control
Time (Hrs)



90 80 70
% Drug Release
60 50 40 30 20 10 0 0 1 2 3 4 5
Solid Dispersion Direct Compression Control
Time (Hrs)
Dissolution Media 70:30 Ethanol:Water HPLC Column 5m CN 250mm x 4.6mm


120
100
% Drug Release
80
60
40
Solid Dispersion Direct Compression
20
Control
0 0 1 2 3 4 5
Time (hrs)


Conclusions For Carbamazepine
Both Lutrol 68 micro and Lutrol 127 micro improved the dissolution of Carbamazepine
Solid dispersion techniques appeared to provide incomplete release of Carbamazepine
Actives
Excipients
Value Added
pharma SOLUTIONS
Case Study 2 Comparing different granulation techniques
Formulation and Process
Made Carbamazepine tablets using different granulation techniques: n Direct Compression n Wet Granulation n Melt Granulation Two ratios evaluated: 1:3 and 1:5 (Drug: Poloxamer) Microprill was used only in Direct Compression Tablets compressed at 400mg, target hardness 5-7Kp
n n
Actives
Excipients
Value Added
Lutrol 68 micro 1:3 Ratio
Carbamazepine and Lutrol F 68 1:3 Ratio

120
100
% Drug Release
80
60
Direct Compression
40
Melt Granulation
20
Wet Granulation Control
0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
Time (Mins)
Lutrol 68 micro 1:5 ratio
Carbamazepine and Lutrol 68 1:5 Ratio

100 90 80 70
% Drug Release
60 50 40 30 20 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
Direct Compression Melt Granulation Wet Granulation Control
Time (Hrs)

120
100
% Drug Release
80
60
Direct Compression
40
Melt Granulation
20
Wet Granulation Control
0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
Time (Hrs)

120
100
% Drug Release
80
60
40
Direct Compression Wet Granulation
20
Melt Granulation Control
0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
Time (Hrs)
n n n n
Actives
Excipients
Value Added
Lutrol 127 micro Dissolution
Comparing 1:5 and 1:3 ratio Lutrol 127 direct compression tablet
90 80 70
% Drug Release
60 50 40 30 20 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
1:5 Ratio Lutrol 127 1:3 Ratio Lutrol 127
Time (Hrs)
Conclusions
Use of poloxamers, regardless of granulation technique, improved the solubility of Carbamazepine. Higher levels of poloxamer create a greater binding effect, which has an impact on dissolution. Microprilled Poloxamers exhibit good blend homogeneity and eliminate the segregation problem during direct compression. The gelling characteristic of microprilled Poloxamer 407 can be used for controlled release or other drug delivery technology. Microprill poloxamer can be a good candidate as a water soluble lubricant for effervescent tablets.
Actives
Excipients
Value Added
ARE THERE ANY QUESTIONS ????

Ibuprofen Formulations Process
Dissolution studies with capsules and tablets were evaluated Tablets compressed using 11mm round flat face bevel edge tooling Target weight 800mg, target hardness 4-5Kp Using Ibuprofen as a model drug dissolution studies were carried out at pH 4.5 (where Ibuprofen has limited solubility)
CRS 2005/ 32nd Symposium on Controlled Release of Bioactive Materials / 18.-22.06.2005 / Miami, Florida, U.S.A.
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pharma SOLUTIONS

Characterization of Newly Developed Micronized Poloxamers for Poorly Soluble Drugs

n Actives n Excipients n Contract Manufacturing n Value Added

Helping make Pharmaceuticals betterTM

Poloxamers Chemical Nature

Helping make Pharmaceuticals betterTM

Lutrol F 68 Lutrol F 127

Helping make Pharmaceuticals betterTM

Brand Name n Lutrol F68NF n Lutrol F127NF

Pharmacopeial Name n Poloxamer 188 n Poloxamer 407

Lutrol F87NF Lutrol L44NF Lutrol F108NF

Poloxamer 237 Poloxamer 124 Poloxamer 338

Helping make Pharmaceuticals betterTM

The character of each poloxamer in terms of:

molecular weight appearance hydrophilicity / hydrophobicity solubility

is determined by the chain length of the

Helping make Pharmaceuticals betterTM

Molecular weight of PO-part

3625 3250 2750 2250 2050 1800 1450 1200 950 0

124 105 108

Percentage EO-part (%)

Poloxamer grades Definition of Number Code

Helping make Pharmaceuticals betterTM

Mw of PO-part EO-part (Wt.%) Poloxamer 18 8 Poloxamer 40 7 18 x 100 = 1800 40 x 100 = 4000 8 x = 7 x = 10 80 10 70

Helping make Pharmaceuticals betterTM

12000 11000 10000

9000 8000 7000 6000 5000 4000 3000 0

L44 L35 F38

Percentage EO-part (%)

Lutrol F Grades Nomenclature

Helping make Pharmaceuticals betterTM

Mw Lutrol F 6 8 6 = x 1000 6000

Lutrol F Grades Molecular Weight

Helping make Pharmaceuticals betterTM

Lutrol F 68 lot-No. 89-0823 lot-No. 87-0807

(Mw/Mn) 1.4 1.4

Lutrol F127 Molecular Weight

Helping make Pharmaceuticals betterTM

Lutrol F 127 lot-No. 41-0805 lot-No. 64-0806

(Mw/Mn) 1.4 1.4

Lutrol F127 Reason for Bimodal Distribution

Helping make Pharmaceuticals betterTM

Helping make Pharmaceuticals betterTM

Unsat. in USP/NF for 407 = 0.048 + 0.017 mEq/g

Actives n Excipients CONFIDENTIAL

Functionality of Poloxamer 407

Helping make Pharmaceuticals betterTM

Helping make Pharmaceuticals betterTM

Helping make Pharmaceuticals betterTM

One Poloxamer molecule

Limiting Aggregation Concentration

Helping make Pharmaceuticals betterTM

From the available literature: Poloxamer 188 (Lutrol F 68)

* Estimated, no published literature.

Lutrol F Grades Applications

Helping make Pharmaceuticals betterTM

Suspension Suspension Stabilizer Stabilizer

Melt //Spray Melt Spray Granulations Granulations

Lutrol F Grades (Poloxamers)

Helping make Pharmaceuticals betterTM

Lutrol F68 Prill Lutrol F127 Prill

Lutrol 68*micro Lutrol 127* micro Particle Size Range

d (0.5) = 50micron d (0.9) = 90 micron

Lutrol 68micro Lutrol 127 micro Particle Size Range