Transcript formulation of levofloxacin as orodispersible tablets using a ready

FORMULATION OF LEVOFLOXACIN AS ORODISPERSIBLE
TABLETS USING A READY-MADE BLEND OF EXCIPIENTS
COMPARED WITH CLASSIC FORMULATION STRATEGIES
ISRAA H. AL-ANI,Ph.D
Faculty of Pharmacy and Medical Sciences
Al-Ahliyya Amman University
Jordan
INTRODUCTION
• Orodispersible tablets (ODTs) are defined as
tablets that disperse or disintegrate in short
time (upto 2minutes) in the mouth prior to
being swallowed, which results in the rapid
dissolution and absorption of the active
pharmaceutical ingredients contained in these
tablets, providing a rapid onset of action.
• ODTs also provide specific advantages to
pediatric and geriatric patient populations,
which can sometimes experience difficulties in
swallowing conventional tablets and capsules .
• A variety of different processes have been
developed for the production of ODTs,
including freeze drying and molding, as well as
several other more conventional methods,
including dry and wet granulation processes
and direct compression.
• The key challenges associated with the
formulation of good ODTs include fast
disintegration times, reasonably sized tablets,
low moisture sensitivity and taste .
What are ready made excipients?
• The International Pharmaceutical Excipients
Council (IPEC) defines excipients as "Substances,
other than the API in finished dosage form, which
have been appropriately evaluated for safety and
are included in a drug delivery system to either
aid the processing or to aid manufacture, protect,
support, enhance stability, bioavailability or
patient acceptability, assist in product
identification, or enhance any other attributes of
the overall safety and effectiveness of the drug
delivery system during storage or use" .
• Co-processing of excipients could lead to the
formation of excipients with superior
properties compared to the simple physical
mixtures of their components. The main aim
of co-processing is to obtain a product with
added value related to the ratio of its
functionality/price.
• Development
of
co-processed
directly
compressible adjuvant starts with the selection of
the excipients to be combined, their targeted
proportion and the selection of preparation
method to get optimized product with desired
physico-chemical parameters, and it ends with
minimizing avoidance with batch-to-batch
variations.
• An excipient of reasonable price has to be
combined with the optimal amount of a
functional material in order to obtain an
integrated product, with superior functionality to
the simple mixture of components.
• This synergistic effect should improve the
quality of the tablet equally in all aspects
ranging from hardness to dissolution and/or
stability.
• Most important characteristics are the binding
and blending properties of the co-processed
excipients, which must be better than those of
a physical mixture of the starting materials.
Cost is another factor to be considered in the
selection of co-processed product.
• Major limitation of co-processed excipient
mixture is that the ratio of the excipients in a
mixture is fixed and in developing a new
formulation, a fixed ratio of the excipients may
not be an optimum choice for the API and the
dose per tablet under development .
• Co-processed adjuvant lacks the official
acceptance in pharmacopoeia. For this reason, a
combination filler-binder will not be accepted by
the pharmaceutical industry until it exhibits
significant advantages in the tablet compaction
when compared to the physical mixtures of the
excipients.
Aim of the work
The aim of this study was to compare the physical
characteristics and dissolution properties of ODTs
prepared using conventional methods with those
prepared using a ready-made mixture of
excipients (PROSOLV® ODT). These comparison
experiments were conducted using levofloxacin
as a model active pharmaceutical ingredient.
Experimental Part
• Levofloxacin: method of analysis and calibration
curve (ICH guideline).
• Formulation of ODT.
- preparation of the powder blends (weighing and
mixing-using Cubic-mixer)
Six formulas were prepared each contained 250 mg
Levof. F1-F5 used physical mixture of Mannitol,
disintegrants, Avicel, aspartam talc and Mg stearate.
And F6 used the ready-made blend.
The target weight was 500 mg.
Small scale of 500 tablets was prepared, then
scaling up was achieved.
- Evaluation of powder blend (particle size
distribution, bulk density , tapped density,
flowability and angle of repose and
percentage comprisibility)
Note: all tests followed USP requirements.
Table (1): The prepared formulas
Ingredients
F1
F2
F3
F4
F5
F6
Levofloxacin
250
250
250
250
250
250
CCS
25
35
35
SSG
25
CP
25
Aspartam
5
5
5
5
5
Talc
8
8
8
8
8
Mannitol
209
209
209
199
149
Avicel®
50
250
®
Mg Stearate
3
3
3
3
3
Total (mg)
500
500
500
500
500
500
Experimental Part
“Particle size distribution (PSD) of a powder, or
granular material, or particles dispersed in fluid,
is a list of values or a mathematical function that
defines the relative amounts of particles present,
sorted according to size.”
• Samples were taken randomly from different
levels of the vessel and were analyzed by laser
diffraction method. (WJL-608 laser particle size
analyzer)
• no further processes were done after mixing.
Experimental Part
• Direct compression of the powder blends.
• Evaluation of the tablets:
- Weight Variation .
- Hardness and Friability .
- Content Uniformity .
- Wetting time (paper and petri dish method)
- In vitro disintegration time (petridish and
disintegrator methods).
* Dissolution test (USP NF 2013, type I
apparatus)
Scaling up
• Three batches were prepared to evaluate
feasibility and coast effectiveness of the work.
They were prepared in
Pharmaceuticals.
• 5 kg batch
• 20 kg batch
• 50 kg batch.
The tablets resulted from 50 kg were also
evaluated for the same parameters.
Results and Discussion
• Evaluation of the powder blend.
1- Particle size distribution : results showed
superior PSD of the ready made blend.
The average PS was smaller and showed higher
uniformity foe F6 with the co-processed excipient.
PSD of F2
45
40
35
30
25
20
15
10
5
0
35
frequency
30
25
20
15
10
5
0
50
100
150
200
250
0
300
0
Particle size(micron)
50
100
150
200
Particle size (micron)
PSD of F3
30
25
Frequency
Frequency
PSD of F1
20
15
10
5
0
0
50
100
150
200
Particle size(micron)
250
300
250
300
PSD of F5
Frequency
45
40
35
30
25
20
15
10
5
0
0
50
100
150
200
250
300
45
40
35
30
25
20
15
10
5
0
0
Particle size (micron)
50
100
70
60
50
40
30
20
10
0
0
150
Particle size (micron)
PSD of F6
Frequency
Frequency
PSD of F4
20
40
60
80
Particle size (micron)
100
120
200
250
Powder characteristics
Table (2) Results of powder Evaluation
Formula code
F1
F2
F3
F4
F5
F6
Bulk Density (g/ml)
0.48
0.47
0.49
0.48
0.58
0.51
Tapped Density (g/ml)
0.55
0.54
0.55
0.56
0.66
0.56
Angle of Repose (degree)
28o
27o
30o
32o
31o
23o
Percentage comprissibility
12.72
12.69
10.90
14.2
12.12
8.93
Hausner ratio
1.14
1.15
1.12
1.16
1.13
1.09
Evaluation of Tablets
Table (3) Results of Evaluation of Tablets
Formula
code
Weight
variation
F1
Pass
F2
Hardness
kg/cm2
Friability
(%)
Wetting
time (sec)
In vitro
DT (sec)
Drug
Content
(%)
3.5±0.51
0.61±0.05
38±1.1
40±1.3
98±1.5
Pass
3.6±0.62
0.60±0.06
48±1.5
45±2.1
99±2.0
F3
Pass
3.4±0.38
0.63±0.09
45±2.0
48±2.0
100±1.1
F4
Pass
3.5±0.44
0.55±0.09
29±1.8
32±1.2
101±0.98
F5
Pass
3.7±0.51
0.52±0.08
35±2.1
36±3.1
98±0.99
F6
Pass
3.2±0.08
0.40±0.01
30±1.5
31±1.3
99±0.5
Drug Dissolution
120
Percent drug dissolved
100
80
F1
F2
60
F3
F4
F5
40
F6
20
0
0
5
10
15
20
25
30
35
40
45
time(minutes)
Fig 1: Dissolution Profile of the six prepared formulas
50
Dissolution of Drug
Formula Code
F1
F2
F3
F4
F5
F6
Percent drug
dissolved
T (5 min)
25±2.0
24±1.8
24±1.2
28±1.9
22±2.0
50±1.8
Higher dissolution rate was achieved in the first five minutes
with F6
All evaluation results above were obtained from the 50-kg
batch
Coast effect and advantages
Preliminary Evaluation of coast:
Time saving: average 3 hours/working day.
Mixing time of F6 is about 1/3 of that of other
formulas.
Preparation and weighing average of 2 hr saving.
Labour : 2 workers less for the major processes.
Energy saving: around 3 hours working/batch.
Materials coast: 30% less.
Conclusion
Using ready-made excipients in formulation of
levofloxacin ODT added an advantage over the
physical mixture of excipients in characteristics
of the result tablets and cost effect.
Acknowledgment
All thanks to my University (Al-Ahliyya Amman University) for
support of scientific research. And to the cooperating
Pharmaceuticals in Jordan for their highly appreciated help in
this work.
Thanks are extended to my colleagues and students who inspire
me all the time.
Thank you For your kind Attention!
You are welcome in Jordan