Advance Module Project RDC 304

Formulation of a Modified Release Dosage Form

Authors:
Joseph Djarnie
Rodrigo H. Snchez S

Class Code
RD2016-2
 I. Introduction

In last five to six decades, a large number of drug products, mainly in the form of tablet and capsule with
controlled release characteristics, had been introduced. Sustained or controlled drug delivery systems can
achieve predictable and reproducible release rates, extended duration of activity for short half life drugs,
potential for cost saving and patentability, decreased toxicity and reduction of required dose, optimized
therapy, and better patient compliance.

Primary objectives of sustained drug delivery systems are to ensure safety and to improve efficacy of drug
and patient compliance, which could be achieved by better control of plasma drug levels and less frequent
dosing. For any sustained release dosage form, it is very important to use the minimum number of
excipients with minimum processing steps to reduce the tablet-to-tablet and batch-to-batch variations,
using direct compression technique as suitable. It has been shown that in aqueous medium the polymer
undergoes a relaxation process resulting in slow direct erosion of the hydrated polymer. As these
mechanisms can operate simultaneously, they will each contribute to the entire drug release rate. In
particular, a careful balance between the diffusion and erosion mechanisms is required to optimize drug
release toward zero-order kinetics.

Among different technologies used in sustained drug delivery, hydrophilic matrix systems are the most
popular because of the simplicity of formulation, ease of manufacturing, low cost, Food, and Drug
Administration (FDA) acceptance and applicability to drugs with wide range of solubility. For the
development of sustained release dosage form, the solubility of drug is one of the limitations for
availability of drug in gastrointestinal (GI) tract.

Matrix systems appear to be a very attractive approach for economic process development and scale up
point of view in sustained release systems. Hydrophilic polymer matrix is widely used for formulating a
sustained release dosage form. It excludes complex production procedure such as coating and
palletisation during manufacturing and drug release of the dosage form. Drug release of these systems is
the consequence of controlled matrix hydration, followed by gel formation, textural/ rheological behavior,
matrix erosion, and drug dissolution and diffusion, the significance of which depends on drug solubility,
concentration, and changes in matrix characteristics.
 II. Procedure

1. Formulation
a. Rationale
According to our art state research, we decided to use a matrix system to reach the target specifications.
Our criteria to choose this system were based on the dissolution profile range depending on polymer
level and its efficacy in direct compression systems.
Initially, we decided to use three different levels of Methacrylic acid (Eudragit), applying direct
compress, applying five fixed pressure forces (5, 10, 15, 20 and 25 KN).

Formulation 1 (mg) % Scale-up Tolerance min max real (gr) Lot.

Caffeine 400 65.0% 200 99.97 199.80 200.20
Eudragit RLPO 75 12.2% 37.5 99.9 37.46 37.54
Lactose SD 80 13.0% 40 99.9 39.96 40.04
MCC102 40 6.5% 20 99.9 19.98 20.02
Mg Stearate 5 0.8% 2.5 99.9 2.50 2.50
PVP 15 2.4% 7.5 99.9 7.49 7.51
Total 615 100%

Formulation 2 (mg) % Scale-up Tolerance min max real (gr) Lot.

Caffeine 400 65.0% 200 99.97 199.80 200.20
Eudragit RLPO 40 6.5% 20 99.9 19.98 20.02
Lactose SD 115 18.7% 57.5 99.9 57.44 57.56
MCC102 40 6.5% 20 99.9 19.98 20.02
Mg Stearate 5 0.8% 2.5 99.9 2.50 2.50
PVP 15 2.4% 7.5 99.9 7.49 7.51
Total 615 100%

Formulation 3 (mg) % Scale-up Tolerance min max real (gr) Lot.

Caffeine 400 65.0% 200 99.9 199.80 200.20
Eudragit RLPO 20 3.3% 10 99 9.99 10.01
Lactose SD 135 22.0% 67.5 99 67.43 67.57
MCC102 40 6.5% 20 99 19.98 20.02
Mg Stearate 5 0.8% 2.5 99 2.50 2.50
PVP 15 2.4% 7.5 99 7.49 7.51
Total 615 100%

Due to lack of API and the required polymer, finally,

Hardness we test
Pressure forceonly two formulations, keeping our pressure
scheme for them. 5 10 15 20 25
Formulation 1
Formulation 2
Formulation 3
 Formulation 1 (mg) % Scale-up Tolerance min max
Caffeine 400 65.0% 200 99.97 199.80 200.20
Eudragit L 100 75 12.2% 37.5 99.9 37.46 37.54
Lactose SD 80 13.0% 40 99.9 39.96 40.04
MCC102 40 6.5% 20 99.9 19.98 20.02
Mg Stearate 5 0.8% 2.5 99.9 2.50 2.50
PVP 15 2.4% 7.5 99.9 7.49 7.51
Total 615 100%

Formulation 3 (mg) % Scale-up Tolerance min max

Caffeine 400 65.0% 200 99.9 199.80 200.20
Eudragit L 100 20 3.3% 10 99 9.99 10.01
Lactose SD 135 22.0% 67.5 99 67.43 67.57
MCC102 40 6.5% 20 99 19.98 20.02
Mg Stearate 5 0.8% 2.5 99 2.50 2.50
PVP 15 2.4% 7.5 99 7.49 7.51
Total 615 100%

III. Equipment

Balance model: METTLER TOLEDO (AB54). TIPT ID #: EB003. Sensitivity: Max 51 gr, Min 10 mg, e
= 1 mg, d = 0.1 mg
Balance model: Sartorius. TIPT ID #: ws97001. Sensitivity: 7200 gr + 0.1 gr
Balance model: AND Electrical Balance. TIPT ID #: ws96003. Sensitivity: Max 6100 gr d = 0.1 gr,
Max 1000 gr d = 0.01 gr
Compression Machine.
High Shear Granulator.
Balance model: Sartorius. TIPT ID #: ws97002. Sensitivity: 16,000 gr + 0.5 gr
UV-VIS Spectrophotometer. TIPT ID #: uv006
LOD model: METTLER TOLEDO HB 43 Halogen. TIPT ID #: TE0601
ROTAP model: RX-29. TIPT ID #: 11488.

Granules Particle Size Distribution

The particle size distribution of samples was determined by ROTAP method. The samples were loaded on
the top US mesh stack. After that tapping and rotational movement were applied.

Sampling and Spectrophotometry

During the testing of percentage label claim, ten sample tablets are taken from our final batches. These
samples are then diluted to a particular strength solution whose absorbance is determined by
Spectrophotometer. The calibration curve is generated by plotting concentration vs. absorbance.
Production of Tablets
After set-up, for engineer batches tablets were produced using increasing compression forces (5, 10, 15,
20, 25 ) for two formulations. Then the tablets were collected and dedusted for analysis.

Determination of Tablet Weight Variation

The tablet weight variation for ten tablets collected from each formulation was determined by using the
electronic balance (Precisa Instruments Ltd., Switzerland; TIPT ID # WS04003). Each time one tablet is
placed on the balance and the value was recorded in mg.

Determination of Tablet Hardness

The hardness for tablets collected from engineer and final test was determined using a hardness tester
(Pharma Test, Germany; TIPT ID # TE0901]). Each time one tablet is placed into the hardness tester and
the value was recorded in SCU.

Method for preparation of sustained release caffeine tablets

Both tablet batch formulations were prepared by direct compression method. API (caffeine) and polymers
(Eudragit L 100) were passed individually through #40 sieves and mixed well for 10 min in V-blender. To
this blend, lactose (diluent) was added after passing through #40 sieves and mixed thoroughly for 5 min.
This powder blend was lubricated with magnesium stearate after passing through #60 sieves and then
directly compressed into tablets using a single punch rotary tablet machine using 10 mm flat punches.
Tablet hardness was controlled during the process.

Bulk density
Apparent bulk density (0) was determined by weighing accurately 25 g of powder (M), which was
previously passed through #40 sieves and transferred in 100 ml graduated cylinder. Carefully level the
powder without compacting, and read the unsettled apparent volume (V0) Calculate the apparent bulk
density in g/ml by the following formula:

Evaluation of compressed tablets

Thickness
The thickness of the matrix tablets was determined using a caliper and the results were expressed as mean
values of 3 determinations, with standard deviations.
Weight uniformity test
Twenty tablets from each batch were weighed using an electronic together and individually, and the mean
weight and % deviations were calculated according to USP.
Hardness measurement
For each formulation, the hardness of 5 tablets was determined using an electronic hardness tester. The
mean crushing strength (hardness) was determined.
Friability
Six tablets were randomly selected from each batch and weighed. The tablets were set to rotate at 25
rpm for 10 min in a friabilitor. Tablets were dusted and reweighed:

Drug content
Accurately weighed the quantity of the tablet powder equivalent to 400 mg of the drug was transferred
to 100 ml volumetric flask. 50 ml of water was added. Mix with the aid of ultrasound for 10 min, and then
the volume was diluted up to 100 ml with the same buffer solution, mixed solution was filtered, 5 ml of
the filtrate was diluted to 100 ml with same buffer solution and examined under U. V Spectrophotometer.
In vitro release studies
In vitro release of caffeine from the tablets was studied using USP Type II dissolution apparatus in 1.2 pH
simulated gastric fluid TS (without enzymes). The volume of the dissolution medium was 900 ml, and the
stirring speed was set at 50 rpm. At predetermined time intervals, 10 ml of sample was withdrawn.
Samples were filtered through 0.45 m membrane and analyzed after suitable dilution. All dissolution
studies were carried out in triplicate.
 IV. Result and discussion

Particle Size Distribution

The change on PSD is explained because of variation on the polymer level.

Heckel plot

Heckel Plot
5.5
5 y = 0.149x + 1.2002
4.5
4
ln(1/1-D)

3.5
3
2.5
2
y = 0.083x + 0.9869
1.5
1
0.5
0 5 10 15 20 25 30
Compression Pressure
F1 Ln(por.) F3 Ln(por.) Linear (F1 Ln(por.)) Linear (F3 Ln(por.))

Bonding capacity

Bonding Capacity Formulation 1

6 y = -0.0938x + 5.9375

4
Ln (TS)

0
0.00 5.00 10.00 15.00 20.00 25.00
% Porosity
 Bonding Capacity Formulation 3
6

5.5

4.5
y = -0.0753x + 5.7548
Ln (TS)

3.5

2.5

2
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00
% Porosity

Due to presence of a plastic polymer, both formulations showed plastic behaviors, increasing their
elasticity when contains more polymer.

Swelling behavior.
To analyze the effect of a acidic solution in the swelling behavior of the tablets, we added 50 ml of
simulated gastric fluid TS (without enzymes) in a petri that contains our tablets.
 Tablet Pressure Force Formulation
(KN)
1 5 1
2 10 1
3 15 1
4 20 1
5 25 1
6 5 3
7 10 3
8 15 3
9 20 3
10 25 3

According to our results, low pressures generates greater swelling effects. This is explained due to
reduction in the porosity, providing less space for the water goes through.
Weight variation

Weight distribution
625.00
620.00
615.00
610.00
Weight (mg)

605.00
600.00
595.00
590.00
585.00
580.00
575.00
F1 F3
Formulation

Label claim

Label Claim
420

410
Concentration (mg)

400

390

380

370

360
F1 F3
Formulation
Hardness
Dissolution Profiles

Dissolution Formulation 1
450.0

400.0

350.0

300.0
Cncentration (mg)

250.0

200.0

150.0

100.0

50.0

0.0
0 20 40 60 80 100 120 140 160 180 200
Time (minutes)

5 KN 10 KN 15 KN Slow release Target Profile Fast release

 Dissolution Formulation 3

450.0

400.0

350.0
Concentration (mg)

300.0

250.0

200.0

150.0

100.0

50.0

0.0
0 20 40 60 80 100 120 140 160 180 200
Time (minutes)

Slow release Target Profile Fast release 5 KN 10 KN 15 KN

According to dissolution profiles results, we can fit the three required profiles in the range of evaluated
formulation/condition.

I. Fulfillment of properties.

The most important property to be faced in this report was to fit within the dissolution profiles. In order
to analyze these profiles we defined average values for the requirement. In next table, they are showed
in same color.
 F1 F3
Slow Target Fast
Time [min] 5 KN 10 KN 15 KN 5 KN 10 KN 15 KN
release Profile release
5 290.9 73.1 75.0 103.7 124.1 63.4
30 352.7 110.0 75.0 120.0 160.0 200.0 180.0 141.0 64.3
60 341.5 204.4 158.4 220.0 260.0 300.0 299.3 236.6 166.8
120 348.1 356.2 219.7 300.0 300.0 310.0 362.3 361.1 264.9
180 360.9 384.3 264.0 320.0 340.0 320.0 393.7 384.1 310.0

Fulfillment of properties.
Target
Values F1 / 10 KN F3 / 10 KN F3 / 10 KN
Tablet Weight 612-618
Dissolution Simulated Gastric fluid (without enzymes)
Friability: <0.5% OK OK OK
Dissolution time
30 min 40-50
Target profile 60 min 65-75 OK
180 min >80
30 min 30-40
Slow release 60 min 55-65 OK
180 min >80
30 min 50-60
Fast release 60 min 75-85 OK
180 min >80

Conclusions

We fulfill the required specifications, nevertheless it was not possible to run a scaled-up batch, due to lack
of ingredients. For this reason, it is not possible ensure that this result would be repeated in future
batches.

The chosen strategy (matrix) is an affordable and inexpensive to produce modified release tablets.
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