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Wet Granulation Resolves Tablet

Reformulation Challenges

Article in Pharmaceutical Technology · April 2017

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Smruti Chaudhari
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Tablet Reformulation

Wet Granulation Resolves

Tablet Reformulation Challenges
Smruti P. Chaudhari

T
he reformulation of a 100-mg tablet into a 300-mg
tablet presented numerous challenges. First, the
original 100-mg formulation of the compound
V_KURASHEV/SHUTTERSTOCK.COM

(Compound X) produced a tablet weighing 370

A case study reviews the reformulation and
scale up of high drug load prototype using wet
granulation process for a model formulation.
mg. Simply tripling the original formulation was not an
option, because doing that would produce a tablet too
large for any patient to take. Second, the total tablet weight
for both strengths, 100 mg and 300 mg, had to be identi-
cal and less than or equal to 550 mg. Third, no new ex-
cipients could be added to the original formulation, as
doing so would detrimentally affect paperwork already
filed with regulatory agencies. The existing formulation
consisted of 28.5% weight per weight (w/w) drug loading
with inactive excipients that included lactose monohy-
drate, croscarmellose sodium, polyvinylpyrrolidone, mi-
crocrystalline cellulose, and magnesium stearate. Finally,
tablet dissolution had to replicate that of the existing
100-mg tablets. Scientists reformulated the 300-mg tablet
to meet the necessary weight and dissolution criteria and
without adding new excipients using the methods described
in this case study.

Smruti P. Chaudhari, PhD, is a development scientist at
Metrics Contract Services.
s42 Pharmaceutical Technology
Reformulation method
Compound X was micronized prior to drug-product manufac-
ture. Following micronization, a wet granulation process was
used to improve the bulk density, powder flow of the formula-
tion, and produce a small tablet with good tableting properties.
The reformulation work was targeted toward investigat-
ing the effect of the following conditions on the wet granula-
tion process and the resulting tablet properties:
t
Increasing the drug load at 40% w/w, 50% w/w, and
60% w/w, respectively
t
The percent w/w of granulating solution used
t
Use of different Comil screens during dry milling
t
Scale up from 5-L to 65-L granulation scale.
The manufacturing process consisted of the following:
t
API was blended with inactive ingredients in the high
shear granulator and granulated using water as the
granulating agent.
t
The wet granules obtained were wet milled and dried
in a fluid bed dryer.
t
The dry granules were milled through Comil
equipped with an appropriate screen.
SOLID DOSAGE DRUG DEVELOPMENT/MANUFACTURING 2017 P h a r mTe c h . c o m
 Figure 1: Schematic representation of the manufacturing procedure.

API Intra-granular excipients

Blending

Granulation (high
shear mixer with
purified water)

Mill wet granules

in Comil equipped
with 375Q screen

Dry granulates in
fluid bed dryer

Mill wet granules in

Comil

39R Screen 50G Screen 55R Screen

Blending with extra- Blending with extra- Blending with extra-

granular excipients granular excipients granular excipients

Compression Compression Compression

Table I: Tablet composition of existing formulation of 100 Figure 2: Effect of drug loading on the dissolution profile.
mg and prototype 1 and 2 of 300-mg tablet formulation.
100-mg 300-mg 300-mg 100
formulation Prototype 1 Prototype 2
Ingredient 80
% Drug released

Amount per Amount per Amount per

tablet (mg) tablet (mg) tablet (mg)
60
Intragranular 40% Drug loading
40 50% Drug loading
Compound X 102.7 308.1 308.1
60% Drug loading
Microcrystalline 18 25.7 0 20
cellulose
0
Croscarmellose 18 25.7 25.7 0 10 20 30 40 50 60 70 80
sodium
Time (Mins)
Polyvinylpyrrolidone 10.8 15.4 15.4
PVP K-30
Lactose 151.1 53.9 105.3
monohydrate
and tablet physical properties of compression forces
Extragranular
and dissolution were analyzed.
Croscarmellose 36 51.4 25.7
sodium Next, selected formulations were packaged as 30 count
Microcrystalline 18 25.7 0 in a 30-cc high-density polyethylene bottle with a 33-mm
cellulose polypropylene induction seal cap. Stability studies were con-
FIGURES ARE COURTESY OF THE AUTHOR

Magnesium stearate 5.4 7.7 5.1 ducted for these tablets at 40 ºC and 75% relative humidity
Opadry coating 10 15.41 15.41 for six months; samples were analyzed at one month, three
suspension months, and six months, respectively.
Total 370 528.9 528.9
Granulation and reformulation
t
The dried-milled granules then were blended with Compound X has poor water solubility; hence, the com-
extra-granular excipients. pound was micronized to increase its solubility. As the
t
Tablets were compressed using a rotary-instrumented average diameter of solid particles decreased, the bulk
tablet press. Blend properties—including bulk density, density of solid particles decreased, resulting in poor flow
tap density, particle size distribution, flowability— of the powder. This was problematic, because powder flow
Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT/MANUFACTURING 2017 s43
Tablet Reformulation
Figure 3: (a) Particle size distribution of the Prototype 2 formulation dictates the quality of the product in terms of its weight
manufactured at 5-L and 65-L scale; (b) Dissolution profile of the and content uniformity. Powder flow also affects manu-
100-mg and 300-mg tablet formulation for Prototype 2. facturing efficiency. Hence, a wet granulation process was
selected for manufacturing.
(a) Granulation is the process of densifying the powder in
which small particles are gathered to form large masses
50
50 known as granules. Granules have better f low as com-
Prototype
Prototype batch
batch
40
40 pared to powders. Two most commonly used granulation
% Retained
% Retained

Scale-up
Scale-up batch
batch
30
30 techniques are wet granulation and dry granulation. The
20
20 granules formed by wet granulation are more compress-
10
10 ible and compactible as compared to granules prepared
00 by dry granulation; therefore, a wet granulation process
was used to manufacture this product using water as a
h

n
es

es

es

es

es

es

Pa
M

granulating agent.
20

40

60

80

0
10

20

Sieve Number
Sieve number
The tablet composition of the existing 100-mg formula-
tion is given in Table I. The tablet weight of existing formu-
(b) lation was 370 mg. Producing a 300-mg tablet formulation
by following the original 100-mg formulation would have
100 produced a tablet weighing 1110 mg, which would cause
80 swallowing difficulties and lead to problems with patient
% Drug released

60 compliance. A reformulation was required.

40
To reduce the tablet weight, granulation was performed
100 mg tablet
20 300 mg tablets
using increased drug loading at 40% w/w, 50% w/w, and
60% w/w, respectively. The weights of the tablets at 40% w/w,
0
0 10 20 30 40 50 60 70 80 50% w/w, and 60% w/w drug loading were 770.3 mg, 616.2 mg,
Time (Mins) and 528.9 mg, respectively. These tablets were manufac-
tured using the same inactive excipients as the original
formulation using single-station manual compression,
Figure 4: Dissolution profile of 100-mg Prototype 1 (a) and thus producing a similar tablet dissolution profile to the
Prototype 2 (b) formulation stability samples stored at 400 ºC and existing 100-mg formulation. Figure 1 provides a schematic
75% relative humidity. view of the manufacturing process. The dissolution profile
of tablets at 40%, 50%, and 60% drug loading is shown in
(a) Figure 2. The tablet with 60% w/w drug loading was chosen
for further studies.
100 After wet granulation of the 60% drug loading formula-
% Drug released

80 tion, the granules were divided into three equal portions

60
and milled through a Comil equipped with a 39R, 50G,
Initial and 55R screen, respectively. The selection of the Comil
40 1 month
screen is crucial in this step, because the non-optimal
20 3 month
6 month screen could ruin the benefits of the granulation.
0 After milling, the different blends were subjected to
0 10 20 30 40 50 60 70 80
Time (mins) Flodex analysis. Of the three screens used to mill the dry
granules, it was observed that granules milled using the
50G screen showed greater flowability as compared to the
(b) 39R and 55R screens; hence, the 50G screen was chosen to
mill the granules in prototype development batches.
100
The 300-mg tablets at 60% drug loading also were manu-
% Drug released

80 factured using rotary press. It showed similar dissolution

60 properties as the existing 100-mg formulation.
40
Initial The 100-mg tablet strength was manufactured using
1 month
3 month
a common blend approach. Granules from the 300-
20
6 month mg tablet strength were diluted with lactose and com-
0 pressed with the same tablet weight as the 300-mg tablet.
0 10 20 30 40 50 60 70 80
Time (mins) Both tablets showed acceptable physical and dissolution
properties.
s44 Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT/MANUFACTURING 2017 P h a r mTe c h . c o m
Prototype batches
Two prototype formulations were manufactured at 60% w/w
drug loading:
t
Prototype 1 contained the inactive excipients lactose
monohydrate, croscarmellose sodium, polyvinylpyrrol-
Figure 5: Dissolution profile of 300-mg Prototype 1 (a) and
Prototype 2 (b) formulation stability samples stored at 400 ºC and
75% relative humidity.
(a)

idone, microcrystalline cellulose, and magnesium stea-

100
rate. This formulation represented all the inactive ex-

% Drug released
80
cipients of the original formulation.
60
t
Prototype 2 contained the inactive excipients lactose
Initial
monohydrate, croscarmellose sodium, polyvinyl- 40
1 month
pyrrolidone, and magnesium stearate. It did not 20 3 month
6 month
contain the microcrystalline cellulose present in the 0
original formulation. 0 10 20 30 40 50 60 70 80
Time (mins)
Inactive excipients can be removed from formulations with-
out adversely affecting analytical methods; it is the adding of
(b)
new inactive excipients that detrimentally affects analytical
methods for the product. 100

Prototype 1 was granulated with 44% w/w water and Pro-

% Drug released
80
totype 2 was granulated with 37% w/w water and compressed 60
using rotary tablet press. Initial
40 1 month
After five minutes of compression, run tablet weight varia- 3 month
20
tion was observed as well as rat-holing in the powder blend, 6 month
which occurs when the central part of the hopper immedi- 0
0 10 20 30 40 50 60 70 80
ately empties, but some blend remains stagnant around the Time (mins)
exterior. To evaluate what was causing this erratic flow of the
blend from the hopper to the die, particle size determination
was conducted, which revealed that these blends had higher 75% relative humidity, respectively. Landln et al (1) studied
percentages of fines, resulting in poor flowability. the effect of microcrystalline cellulose on the tabletability
To reduce the number of fines in the granulation, more and stability of prednisolone formulations. It was found that
robust granules had to be made, which was accomplished by when microcrystalline cellulose tablets are stored under
adding more water for granulation. Water for granulation was high humidity conditions, formulation undergoes signifi-
increased at 65L granulation scale, which made more robust cant changes in mechanical and drug release properties,
granules and reduced the number of fines. which are attributed to interaction between microcrystal-
The bowl size was increased to 65L to scale up the formu- line cellulose and water. The total impurities did not change
lation. Comparison of the particle size analysis of granules in both prototypes during storage.
manufactured at 5-L scale and 65-L scale is provided in Figure 3. Prototype 2 was granulated with 45% w/w water at 65-L
As the water for granulation was increased, there was a greater granulation scale and dried and milled through Comil
proportion of granules to fines. The granules manufactured equipped with 50G screen. The scale up Prototype 2 batch
in the 65-L bowl showed 25% of fines; granules manufactured was compressed in rotary press and it showed good flowabil-
at 5-L scale showed almost 45% of fines. The tablets prepared ity and similar dissolution profile.
at 65-L scale had acceptable tablet physical and dissolution
properties. The dissolution profiles of the 100-mg and 300-mg Conclusion
formulations and its stability are shown in Figure 3b. The reformulation was successful because all criteria established
The amount of water added to the granulation determined were met. Tablets of 100-mg and 300-mg dosage were formu-
the flow property of the granules. The endpoint of granula- lated and the final weights for both the 100-mg and 300-mg
tion was determined in a traditional way, in which a small tablets were identical and less than 550 mg. Dissolution of both
amount of sample was taken and compacted by hand to find the 100-mg and 300-mg strength tablets were similar to the
out if the end of granulation was reached. This method lacks original formulation. Not only were no new excipients incorpo-
accuracy and reproducibility. A new method needs to be de- rated, but one excipient in the original formulation was excluded
veloped to accurately determine the endpoint of granulation. in the final re-formulated product because it did not provide
Stability studies conducted on both prototype batches any added properties.
revealed that Prototype 1 tablets showed slowing of dis-
solution upon aging; Prototype 2 was selected for scale-up Reference
studies. Figure 4 and Figure 5 show the dissolution profiles of 1. M. Landln, et al., International Journal of Pharmaceteutics, 91(2–3)
100-mg and 300-mg stability samples stored at 400 °C and 143-149 (1993). PT

Pharmaceutical Technology SOLID DOSAGE DRUG DEVELOPMENT/MANUFACTURING 2017 s45

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