(767g) Microcrystalline Cellulose – Does Wood Pulp Source Impact the Direct Compression Performace of This Excipient?

 

INTRODUCTION

 

 

In a quality by design (QbD) environment knowledge and understanding of
raw material critical quality attributes (CQAs) are essential [1]. Excipient variability is an
important consideration particularly when blended with challenging APIs where
manufacturing may occur close to the edge of failure, i.e. close to the acceptance
limits for critical quality attributes. In such cases small variations in an
excipients attribute could possibly impact the end product quality, even if the
variation is within the excipient’s certificate of analysis release
specifications. Continuous process improvement, continuous manufacturing and regulatory
requirements for improved process understanding as covered by ICH Q10 [2] drive a need to understand the
impact of excipient variability on finished product performance.

Microcrystalline cellulose (MCC) was chosen as the excipient of study due
to its widespread use as a diluent/filler or binder in solid oral dosage form
manufacturing. MCC has been available as a pharmaceutical excipient since 1964 [3] and consequently there has
been much previous research into its material attributes. Moisture [4], crystallinity [5-7], degree of polymerisation
(DP) [3], surface area and porosity [4] have been suggested in the
literature as material attributes for consideration when processing MCC.

In order to
understand the possible variability in MCC it is important to understand its manufacturing
process. Pharmaceutical cellulose is derived from wood pulp. Trees are broken
down into wood chips which undergo a chemical process known as the ‘Kraft
process’[8] which removes the lignin that links cellulose chains together as
wood. Wood pulp is the starting material bought by MCC manufacturers. The type
of wood source (soft/hard woods) will affect the chemical content (the
hemicellulose content and crystallinity) of the wood pulp.

MCC manufacturers
treat the wood pulp with acid to breakdown the long cellulose chains into
smaller chain lengths (reduce the degree of polymerization). Acid hydrolysis
cleaves the long cellulose chains at amorphous sites where hemicellulose sugar
chain branches are located. Therefore how the cellulose is hydrolysed is
dependent on its chemical content and the number of amorphous regions. The length
of the hydrolysis time and final DP of a batch of MCC is influenced by the wood
pulp type as different wood pulps have characteristic leveling off degrees of
polymerization e.g. 180-210 for hard woods and 210-250 for soft woods [3]. By blending different wood pulps together before hydrolysis the DP
can be predicted by manufactures. This is an important control as it can
influence the MCC final bulk density[3]. The resulting shorter cellulose chains are thus more crystalline
as the amorphous regions have been cleaved, hence the name microcrystalline
cellulose. Post hydrolysis steps (spray
drying/air stream drying and sieving) offer manufactures the opportunity to
manipulate the final lot bulk density, PSD and mean particle size to produce
product within specification.

The study presented aims to understand if samples
of MCC grade PH102 produced from different wood pulp mixes show differences in
physicochemical properties and hence compaction performance during a direct
compression process.

 
Materials and Methods

 

 

Three batches of MCC
PH102 produced from a range of pulp sources were supplied by FMC. The pulp
types have not been disclosed due to commercial sensitivity.  All samples were
produced using the commercial scale process and meet with supplier and
pharmacopeia specifications.

·        
Sample 1 - 75% Pulp X: 25% Pulp Y

·        
Sample 2 - 50% Pulp X: 50% Pulp Z

·        
Sample 3 - 100% Pulp X

MCC PH102 lots
were characterized and compared for differences in particle size distribution
(sieve analysis), moisture content (thermogravimetric analysis), crystallinity
(FTIR) and surface area (BET N₂ adsorption), degree of
polymerization and scanning electron microscopy.

Two
compaction studies were carried out on an instrumented Piccola™ rotary tablet
press. The first compaction study was on samples ‘as received’. The second compaction
study was performed on a sieved size fraction (106-250 μm) of each lot in
order to remove the confounding factor of particle size distribution
differences. Compacted material hardness, weight and thickness were measured on
a Pharmatron™ Smart Test 50 and compaction profile generated.

 

 

RESULTS
AND DISCUSSION

The particle
size distribution (PSD) profiles of each sample as received did indicate a
significant difference in PSD particularly the % fines. The sieved size
fraction (106-250 μm) of each sample was then compared in order to
eliminate the influence of PSD and % fines as a possible reason for differences
in the compressibility of the lots.

Characterization
of the 106-250 μm size fractions for each sample identified differences in the surface
area, crystallinity and bulk density (Table 1) and the PSD (Figure 1). All lots
had a moisture content determined by loss on drying in the range 3.74 - 4.86%
w/w.  It was assumed that within this range moisture was not an influencing
factor [4].

When comparing compression
profiles of samples (Figure 2), Samples 1 and 2 which were
manufactured from pulp mixes were similar. However Sample 3, manufactured form
100% of pulp X, showed a significantly higher compressibility.  

The study
results show that particle size is a major factor that influences MCC
compressibility. Following correction for particle size, Sample 3 produced from
a single pulp source showed superior compression properties. The particle
properties resulting in this increase in compaction are currently inconclusive
and being explored. Further studies will focus on degree of polymerization and
particle mechanical parameters during compression.

CONCLUSIONS

 

 

Previous studies
[9, 10] have discussed wood pulp as a source of variability between batches
of MCC. Mixing wood pulps minimizes this variability.  In this study a MCC
sample produced from 100% of one particular wood pulp during manufacture of MCC
produced material which performed differently during direct compression
compared to samples from pulp mixes when corrected for difference in particle
size between samples.  

The impact of
this variability in MCC will be formulation specific. It is envisaged for
blends with a high % API loading which is difficult to compact, this
variability may be significant to drug product manufacturers. This also
highlights the importance of using a number of different lots of excipients
during drug development to capture excipient variation where it is potentially
a risk factor.  

 

 

ACKNOWLEDGMENTS

 

 

This research is funded by the Synthesis
and Solid State Pharmaceutical Centre (SSPC) and Science Foundation Ireland
(SFI) under grant number 12/RC/2275. PH102 was donated by FMC Corporation. 

 

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8.             Chakar, F.S. and A.J.
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9.             Landin, M., et al., Effect
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Table 1.
Characterization results of the 106-250 μm size fraction for each of the three samples before compression.

	SAMPLE 1	SAMPLE 2	SAMPLE 3
Moisture %w/w	4.41 ± 0.68	4.86 ± 0.64	3.74 ± 0.36
Bulk density g/cm3	0.32	0.32	0.34
IR Crystallinity (Nelson et al 1964, )	0.86	0.90	0.94
Surface Area m2/g	1.232	1.148	1.289
D50 μm	174 ± 0.00	212 ± 3.46	186 ± 1.53

Figure 1.
Malvern PSD of 106-250 μm size fraction comparison for the three samples. Sample 1 (green),
sample 2 (blue) and sample 3 (red). 

Figure 2. Compression
profiles for the three samples. Tensile strength for N=20 tablets