Technical Information
Ibuprofen DC 85
April 2010
Supersedes issue dated January 2010
03_060201e-07/Page 1 of 16
®=R
egistered trademark of BASF group
Pharma Ingredients
& Services
03_060201e-07 April 2010
Page 2 of 16
Ibuprofen DC 85
General Information
It is a current trend in the pharmaceutical industry to simplify the manufacturing
process of pharmaceutical formulations and thus to reduce the costs of manu­
facturing.
So-called direct compression grades (DC grades) can be used to produce tablets
without any previous granulation or compaction process. In some cases, small
amounts of additional excipients should be added and blended with the DC grade.
It is also possible to compress the DC grades without any additional substances.
Many Ibuprofen DC grades are in the market, mostly from Asian producers.
The BASF product Ibuprofen DC 85 distinguishes itself from its competitors allowing
the use of high-speed compression processes and by eliminating sticking on the
tablet tools.
Ibuprofen DC 85 means: the composition contains 85% pure Ibuprofen and 15%
of inactive ingredients.
If necessary, Ibuprofen DC 85 can be diluted by additional inactive ingredients and
combined with other active ingredients.
The medical indication, given in the next chapter, is generally applicable for the
administration of Ibuprofen.
1. Medical indication
Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal
anti-inflammatory drugs (NSAIDs).
Due to its analgesic, antipyretic and anti-inflammatory actions it is used in the
treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis,
ankylosing spondyolitis, mild and moderate pain, dysmenorrhoea, vascular headache
and fever.
The application of Ibuprofen as a pain reliever or an antipyretic needs only low
dosages (200 – 400 mg). The dose level as an anti-rheumatic for adults is about
1.2 to 3.2 g orally per day in 3 or 4 divided doses.
The common dosage ranges are tablets with 200 mg, 400 mg, 600 mg and 800 mg
and slow release tablets with 800 mg. The OTC dosage forms are mainly the 200 mg
and 400 mg forms (except for the United States and other countries, here the
200 mg form is the only OTC form).
Ibuprofen is often combined with oral decongestants and cough and cold drugs.
Other forms are syrups, suspensions and topical dosage forms like creams.
Pharmacology
The mode of action is believed to involve the reversible inhibition of the enzyme
cyclooxygenase (COX) which is responsible for the biosynthesis of prostaglandins
(PGs) from arachidonic acid in the cellular membrane.
Prostaglandins are distributed in the various tissues, and have among other properties
a powerful effect on the smooth muscles.
In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized
in increased amounts and sensitise the tissues to the action of other agents such
as histamine and kinins. Therefore the symptoms like pain and inflammation appear.
The incidence of fever is raised by the influence of the PGs on the heat regulation
centre in the hypothalamus. There they scale up the normal set point of 37 °C.
The inhibitory action of NSAIDs on PG synthesis is also the most probable cause
of the gastrointestinal side effects.
PGs play an important role for physiological functions, like the synthesis of protective,
alkaline secretion in gastric mucosa cells. The inhibition of the PG synthesis means
an absence of protection of the gastric mucosa and this may lead to sickness,
abdominal pain and ulcers.
But among the NSAIDs Ibuprofen has the best benefit to risk profile and the lowest
incidence of serious gastrointestinal adverse effects.
Pharmacokinetics
Ibuprofen is readily absorbed by the gastrointestinal tract. The peak plasma levels
are reached within 1 – 2 h. After an oral dose of 200 – 400 mg, 15 – 25 mg/ml
appear in the blood serum. Ibuprofen has an extensive protein binding capacity (99%).
Ibuprofen is excreted via the kidneys. The biological half-life is about 2 hours.
After 24 h 100% of the active substance is excreted in the urine.
03_060201e-07 April 2010
Page 3 of 16
Ibuprofen DC 85
2. Chemical information
Name
The name of the main component is Ibuprofen. The quantity of the active drug
substance is exactly 85 ± 3%
Chemical name of the active drug substance
(2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid
CAS-No.
15687-27-1
EINECS-No.
239-784-6
Synonymous names
(±)-2-[4-(2-methylprpyl)phenyl]propanoic acid
(±)-Benzeneacetic acid, -methyl-4-(2-methylpropyl)
(±)-p-Isobutylhydratropic acid
(±)-2-p-Isobutylphenyl)propionic acid
Ibuprofen is the racemate of (+)-Ibuprofen and (-)-Ibuprofen (optical rotation[]D = 0 ° ).
The pharmacologically active form is (+)-Ibuprofen. According to the literature
(“Ibuprofen: a critical bibliographic review”, K. D. Rainsford, Taylor & Francis
Ltd., London 1999, page 104) approximately 30 to 70% of the (-)-Ibuprofen is
converted to the active form (+)-Ibuprofen in the body.
This process proceeds solely from the (-)- form to the (+)- form.
Structural formula
Empirical formula
C13H18O2
Molecular weight
206.28 g/mol
3. Grades
PRD-No.
30255646
Ibuprofen DC 85
50 kg
2 kg (sample)
Retest period
See separate documentation: "Q&R PI (not for regulatory purposes)“ available
at BASF‘s WorldAccount: https://worldaccount.basf.com (registered access).
4. Physical and chemical
properties
Appearance:
Color:
granules with a broad particle size distribution
white to almost white
Odor:
Melting range:
characteristic
DC grade contains several chemical substances, therefore
melting point or range doesn’t make any sense
insoluble until sparingly soluble
Solubility in water:
03_060201e-07 April 2010
Page 4 of 16
Ibuprofen DC 85
5. Regulatory status
Ibuprofen DC 85 is a formulation of Ibuprofen with excipients. A regulatory technical
package is available that includes
- Exact composition
- Manufacturing process
- Analytical method for the DC grade including methods for stability tests
- Stability report
- Specifications of the used active drug substance and the inactive excipients
-General statement, that the used active substance and the inactive excipients
comply with the corresponding specifications
A US-DMF is available upon request.
The active drug substance for Ibuprofen DC 85 is Ibuprofen. The Ibuprofen used
meets specifications of the current editions of Ph. Eur., USP and JP. A CEP is
available and DMFs are active in Europe and the US.
6. Specification
See separate document: “Standard Specification (not for regulatory purposes)“
available via BASF’s WorldAccount: https://worldaccount.basf.com (registered
access).
7. Product characterization
(not part of specification)
Identification
Content of Ibuprofen
Bulk density
Tapped density
Loss on drying
Flowability
Particle size
IR-Spectrum
[%]
[g/ml]
[g/ml]
[%]
[°]
[%]
Must comply
85.0
0.55
0.64
0.89
33.0 free flowing
>1400 µm
0.1
1400 – 1180 µm
4.5
1180 – 1000 µm
26.2
1000 – 850 µm
16.0
850 – 300 µm
48.3
300 – 180 µm
3.4
<180 µm
0.6
03_060201e-07 April 2010
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Ibuprofen DC 85
Particle distribution
The roughly D 50 value of particle size distribution is 700 – 800 µm.
SEM photograph of particles
Ibuprofen DC 85 does not contain a lubricant like magnesium stearate, stearic
acid, sodium stearyl fumarate or others. Mixtures with such kind of lubricants
lead to a physical changing of Ibuprofen until becoming a liquid. Therefore, to
avoid a lumping of Ibuprofen DC 85 over a long storage time, the DC grade doesn’t
contain any lubricant.
03_060201e-07 April 2010
8. Application examples
Page 6 of 16
Ibuprofen DC 85
General impression of reducing manufacturing steps by using Ibuprofen DC 85
Steps by wet granulation (main process for Ibuprofen tablets)
1. Weighing in of all ingredients
2. Preparing of granulation solution
3. Granulation process
4. Wet sieving process
5. Drying of the granules
6. Sieving of the dried granules
7. Adding of the outer phase
8. Final blending to granules ready for compression
9. Compression into tablets
Steps by dry compaction (often used in the latest times)
1. Weighing in of all ingredients
2. Blending of ingredients
3. First compaction run
4. Milling and sieving of the compacted materials
5. Second compaction run of the fines
6. Milling of the secondly compacted material
7. Adding of the outer phase
8. Final blending to granules ready for compression
9. Compression into tablets
Steps by using Ibuprofen DC 85
1. Weighing in of the DC grade (optionally weighing of a lubricant)
2. Optional blending with lubricant
3. Compression into tablets
8.1 Use of lubricants
As generally known, Ibuprofen is not compatible with the most used lubricants like
magnesium stearate, stearic acid or sodium stearyl fumarate, which is demon­strated
by lowering the melting point of Ibuprofen until becoming a liquid in some cases.
But that is not the case during compression into tablets with a quantity of 0.5%
magnesium stearate.
The pure Ibuprofen DC 85 can be compressed into tabletts without any lubricant
or by adding 0.5% Magnesium stearate. If the DC grade is diluted with other inactive
excipients or other drug substances, certain quantities of lubricants could be used.
The following design was tested for lubrication:
Blend
Ibuprofen
DC 85 [%]
Mgstearate
[%]
Lutrol F127 Lutrol F68
micro [%] micro [%]
PRUV [%]
sodium
stearyl
fumarate
0
100
-
-
-
-
1
99.5
0.5
-
-
-
2
98.0
2.0
-
-
-
3
96.0
4.0
-
-
-
4
99.5
-
0.5
-
-
5
98.0
-
2.0
-
-
6
96.0
-
4.0
-
-
7
99.5
-
-
0.5
-
8
98.0
-
-
2.0
-
9
96.0
-
-
4.0
-
10
99.5
-
-
-
0.5
11
98.0
-
-
-
2.0
12
96.0
-
-
-
4.0
03_060201e-07 April 2010
Page 7 of 16
Compression trials
Turbula Blender T2C
Compression
22 Upm
Rotary press Korsch
Compression force
PH 100/6
15 kN
30 rpm
Tablet tools
9 mm
round, light curvation without engravings
Characteristic of tablets
Ejection force
Hardness
Ibuprofen DC 85
[N]
[N]
tablet press
hardness tester
Korsch PH 100/6
Erweka
Results
The previous results demonstrate, that the higher the content of lubricants is, the
lower the ejection forces for the tablets. But with higher quantities the tendency of
sticking increases.
No. of
trial
0
Lubricant
Quantity of
lubricant
[%]
Ejection
force [N]
Time of
compressing
[min]
Sticking
[yes/no]
-
-
265
30
no
0.5
230
30
no
2.0
160
30
no
4.0
130
10
yes
0.5
240
30
no
2.0
220
15
yes
4.0
170
5
yes
0.5
240
30
no
2.0
210
15
yes
4.0
170
5
yes
0.5
220
30
no
2.0
180
30
no
4.0
160
30
no
1
2
Mg-stearate
3
4
5
6
7
8
9
10
11
12
Lutrol® F127
micro
Lutrol F68
micro
Sodium stearyl
fumarate
8.1.1 Long time compression test
Previous trial was independently performed on a rotary press Korsch PH100/6
with 30 rpm and compression force of 15 kN for 5 hours.
Results
Absolute no sticking could be observed.
Despite of good results by compressing tablets over more than 5 hours, BASF
recommends to use magnesium stearate in low quantities of 0.25 to 0.5%.
8.2 Other excipients to dilute
Ibuprofen DC 85
Ibuprofen DC 85 was diluted with additional excipients like microcrystalline cellu­
lose, corn starch, lactose and others. The examples are discribed under items
8.2.1 to 8.2.4.
03_060201e-07 April 2010
8.2.1 Formulation with
microcrystalline cellulose
Page 8 of 16
Ibuprofen DC 85
Ibuprofen DC 85 formulation 1, single punch press
Ibuprofen DC 85
Microcrystalline cellulose
Crosslinked sodium carboxymethylcellulose
Silica
Magnesium stearate
Sum
[%]
200 mg
400 mg
88.24
7.76
3.00
0.50
0.50
100.00
235.3
20.7
8.0
1.3
1.3
266.6
470.6
41.4
16.0
2.6
2.6
533.2
Tablet press:
Excenter Korsch EK0
Compression tools:
1
Compression speed:
30 Upm (1,800 tablets/h)
Compression force:
15 kN
200 mg
Characteristics of tablets
400 mg
Hardness
[N]
121
156
Friability
[%]
0.05
0.15
[min]
3:49
3:21
75.5
78.9
10 min
98.9
98.5
15 min
101.2
100.8
30 min
102.0
101.8
Disintegration
Dissolution
5 min
[%]
03_060201e-07 April 2010
8.2.2 Formulation with corn (maize)
starch
Page 9 of 16
Ibuprofen DC 85
Ibuprofen DC 85 formulation 2, single punch press
[%]
200 mg
400 mg
88.24
235.3
470.6
Corn starch
7.76
20.7
41.4
Crosslinked sodium carboxymethylcellulose
3.00
8.0
16.0
Silica
0.50
1.3
2.6
Magnesium stearate
0.50
1.3
2.6
100.00
266.6
533.2
Ibuprofen DC 85
Sum
Tablet press:
Excenter Korsch EK0
Compression tools:
1
Compression speed:
30 Upm (1,800 tablets/h)
Compression force:
15 kN
Characteristics of tablets
200 mg
400 mg
Hardness
[N]
92
111
Friability
[%]
0.06
2.35
[min]
3:22
2:44
82.6
85.8
10 min
97.7
97.8
15 min
100.3
98.4
30 min
99.0
99.1
Disintegration
Dissolution
5 min
[%]
03_060201e-07 April 2010
8.2.3 Formulation with lactose
Page 10 of 16
Ibuprofen DC 85
Ibuprofen DC 85 formulation 3, single punch press
[%]
200 mg
400 mg
88.24
235.3
470.6
Lactose
7.76
20.7
41.4
Crosslinked sodium carboxymethylcellulose
3.00
8.0
16.0
Silica
0.50
1.3
2.6
Magnesium stearate
0.50
1.3
2.6
100.00
266.6
533.2
Ibuprofen DC 85
Sum
Tablet press:
Excenter Korsch EK0
Compression tools:
1
Compression speed:
30 Upm (1,800 tablets/h)
Compression force:
15 kN
Characteristics of tablets
200 mg
400 mg
Hardness
[N]
86
99
Friability
[%]
0.05
2.6
[min]
3:14
2:07
79.8
84.8
10 min
98.7
96.3
15 min
100.5
99.0
30 min
101.9
99.3
Disintegration
Dissolution
5 min
[%]
03_060201e-07 April 2010
8.2.4 Formulation with microcryst.
cellulose and Kollidon® CL
instead of AcDiSol
Page 11 of 16
Ibuprofen DC 85
Ibuprofen DC 85 formulation 4, single punch press
200 mg
400 mg
88.24
235.3
470.6
Microcrystalline cellulose
7.76
20.7
41.4
Crosslinked Kollidon
3.00
8.0
16.0
Silica
0.50
1.3
2.6
Magnesium stearate
0.50
1.3
2.6
100.00
266.6
533.2
[%]
Ibuprofen DC 85
Sum
Tablet press:
Excenter Korsch EK0
Compression tools:
1
Compression speed:
30 Upm (1,800 tablets/h)
Compression force:
15 kN
Characteristics of tablets
200 mg
400 mg
Hardness
[N]
117
178
Friability
[%]
0.01
0.12
[min]
3:33
3:12
75.4
82.2
10 min
96.8
97.9
15 min
100.0
99.6
30 min
101.3
100.0
Disintegration
Dissolution
5 min
[%]
03_060201e-07 April 2010
9. Production tests on
high-­performance rotary
com­pressing machines
Page 12 of 16
Ibuprofen DC 85
9.1 Compression on a Korsch PH 106 (lab machine)
9.2 Compression on a Fette 1200i at an European toll manufacturer
9.3 Compression on a Fette 3090 high speed rotary press in BASF plant
Shreveport
9.1 Compression on a Korsch PH
100/6 (lab machine)
9.1.1 Formulation with
microcrystalline cellulose
Ibuprofen DC 85 formulation 5, standard rotary press
[%]
200 mg
Ibuprofen DC 85
88.24
235.3
Microcrystalline cellulose
7.76
20.7
Crosslinked sodium carboxymethylcellulose
3,00
8.0
Silica
0.50
1.3
Magnesium stearate
0.50
1.3
100.00
266.6
Sum
Tablet press:
Korsch PH 106
Compression tools:
6
Compression speed:
30 Upm (10,800 tablets/h)
Compression force:
15 kN
Characteristics of tablets
200 mg
Hardness
[N]
85
Friability
[%]
<0.1
[min]
2:24
Disintegration
Dissolution
[%]
5 min
87.6
10 min
98.9
15 min
99.0
30 min
100.6
03_060201e-07 April 2010
9.1.2 Ibuprofen DC 85 blended with
0.5% magnesium stearate
Page 13 of 16
Ibuprofen DC 85
Ibuprofen DC 85 formulation 6, rotary press
[%]
Ibuprofen DC 85
99.50
Magnesium stearate
0.50
Sum
100.00
Tablet press:
Korsch PH 106
Compression tools:
6
Compression speed:
30 Upm (10,800 tablets/h)
Compression force:
10 kN
Characteristics of tablets
200 mg
Hardness
[N]
54
Friability
[%]
< 0.1
[min]
2:16
Disintegration
Dissolution
5 min
9.1.3 Ibuprofen DC 85 without
any lubricant
[%]
86.5
10 min
98.8
15 min
99.8
30 min
100.2
Ibuprofen DC 85 formulation 7, rotary press
[%]
Ibuprofen DC 85
100.00
Sum
100.00
Tablet press:
Korsch PH 106
Compression tools:
6
Compression speed:
30 Upm (10,800 tablets/h)
Compression force:
10 kN
Characteristics of tablets
227 mg
Hardness
[N]
47
Friability
[%]
0.71
[min]
1:38
Disintegration
Dissolution
5 min
10 min
15 min
30 min
[%]
91.8
100.8
102.2
102.5
All trials were performed over 6 hours without any sticking and interruption.
Trial 9.1.3 demonstrates that Ibuprofen DC 85 can be compressed into tablets
without any lubricant.
03_060201e-07 April 2010
9.2.1 Ibuprofen DC 85 diluted to
75% active substance,
manufactured at a
European toll manufacturer
Page 14 of 16
Ibuprofen DC 85
Ibuprofen DC 85 formulation 8, batch size 200 kg
[%]
200 mg
Ibuprofen DC 85
88.24
235.3
Microcrystalline cellulose
7.76
20.7
Crosslinked sodium carboxymethylcellulose
3. 00
8.0
Silica
0.50
1.3
Magnesium stearate
0.50
1.3
100.00
266.6
Total
Tablet press:
Fette 1200i
Compression tools:
24
Compression speed:
60 – 80 rpm
(90,000 – 120,000 tablets/h)
Compression force:
15 kN
Characteristics of tablets
Dosage
[mg]
200
Hardness
[N]
65
Friability
[%]
0.46
[min]
1:21
Disintegration
Dissolution
5 min
10 min
15 min
30 min
[%]
87.3
101.0
101.3
101.5
No sticking and no interruption occured over the entire batch size
9.2.2 Ibuprofen DC 85 +
0.5% magnesium stearate,
same machinery as in 9.2.1
Ibuprofen DC 85 formulation 9, batch size 200 kg
[%]
200 mg
Ibuprofen DC 85
99.50
235.3
Magnesium stearate
0.50
1.2
Total
100.00
236.5
Tablet press:
Fette 1200i
Compression tools:
24
Compression speed:
60 – 80 rpm
(90,000 – 120,000 tablets/h)
Compression force:
15 kN
Characteristics of tablets
Dosage
[mg]
200
Hardness
[N]
65
Friability
[%]
0.46
[min]
1:21
Disintegration
Dissolution
5 min
10 min
15 min
30 min
[%]
87.3
101.0
101.3
101.5
03_060201e-07 April 2010
Page 15 of 16
Ibuprofen DC 85
No sticking and no interruption over the entire batch size
9.3. C
ompressing on a high speed
rotary press at a BASF plant
Batch size: 500 kg each
Study design:
Study Ibu DC +
No.: excipients
dosage
Batch
size
Percen- Compression Comment
tage of speed
Drug/
tablet
1
Pure DC grade 200 mg 500 kg
+ 0.5% Mg
stearate
~85% 700,000
Continuous compression
tablets/hour of tablets. No interruption,
no sticking
2
Pure DC grade 400 mg 500 kg
+ 0.5% Mg
stearate
~85% 720,000
Continuous compression
tablets/hour of tablets. No interruption,
no sticking
3
Ibu DC grade
+ additional
ingredients*
200 mg 500 kg
75% 750,000
Continuous compression
tablets/hour of tablets. No interruption,
no sticking
4
Ibu DC grade
+ additional
ingredients*
400 mg 500 kg
75% 750,000
Continuous compression
tablets/hour of tablets. No interruption,
no sticking
* Additional ingredients: 0.5% Magnesium stearate, 7.8% Avicel PH 102,
3% Ac-Di-Sol, 0.5% Aerosil 200
Compression conditions:
Rotary press: Fette 3090 with 61 compression tools and 2 compression stations
Compression speed: upper limit with 750,000 tablets per hour
Tools: 2
00 mg dosage Ø 9 mm, concave without engravings
400 mg dosage, oval shaped, 14 mm x 8.5 mm
Parameters
Comment
Flowability
free-flowing (angle of repose: 33°)
Drug release
very fast (85% within 5 minutes)
Compression speed
(200 mg tablets)
very high < 700,000 tabs/h
stable process
Compression speed
(400 mg tablets)
very high: 700 – 750,000 tabs/h
stable process
Compression force
11 – 15 kN (which is relatively low for Ibuprofen
compression)
In vitro dissolution profile of tablets produced on Fette 3090
03_060201e-07 April 2010
Summary
Page 16 of 16
Ibuprofen DC 85
•
•
•
•
•
•
Ibuprofen DC 85 is a direct compression grade with 85% Ibuprofen
Ibuprofen DC 85 is a product with modified surface
Ibuprofen DC 85 does not show any sticking tendency during compression
Ibuprofen DC 85 is able to be compressed into tablets without any lubricant
Different lubricants in low concentrations can be used
Ibuprofen DC 85 can be diluted with other excipients to the requested content
of the active ingredient
• Ibuprofen DC 85 can be compressed with high compression speed
• Documentation for registration can be provided to customers
NoteThis document, or any answers or information provided herein by BASF, does not
constitute a legally binding obligation of BASF. While the descriptions, designs, data
and information contained herein are presented in good faith and believed to be
accurate, it is provided for your guidance only. Because many factors may affect
processing or application/use, we recommend that you make tests to determine
the suitability of a product for your particular purpose prior to use. It does not relieve
our customers from the obligation to perform a full inspection of the products upon
delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS
OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS
FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED
OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS,
DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE
INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE
DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED
A PART OF OUR TERMS AND CONDITIONS OF SALE.
April 2010
BASF SE - Care Chemicals Division - Pharma Ingredients & Services - 67117 Limburgerhof - www.pharma-ingredients.basf.com