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.   

REFERENCES

1.             Chen, Z., D. Lovett, and J. Morris, Process analytical technologies and real time process control a review of some spectroscopic issues and challenges. Journal of Process Control, 2011. 21(10): p. 1467-1482.

2.             ICH, Pharmaceutical Quality System Q10, in ICH Q10, I.C.o.H.o.T.R.f.R.o.P.f.H. Use, Editor 2008, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

3.             Thoorens, G., et al., Microcrystalline cellulose, a direct compression binder in a quality by design environment-A review. Int J Pharm, 2014. 473(1-2): p. 64-72.

4.             Sun, C.C., Mechanism of moisture induced variations in true density and compaction properties of microcrystalline cellulose. Int. J. Pharm., 2008. 346(1-2): p. 93-101.

5.             Park, S., et al., Cellulose crystallinity index: measurement techniques and their impact on interpreting cellulase performance. Biotechnol Biofuels, 2010. 3: p. 10.

6.             Mihranyan, A., et al., Moisture sorption by cellulose powders of varying crystallinity. Int. J. Pharm., 2004. 269(2): p. 433-442.

7.             Rowe, R.C., A.G. McKillop, and D. Bray, The effect of batch and source variation on the crystallinity of microcrystalline cellulose. Int. J. Pharm., 1994. 101(1-2): p. 169-72.

8.             Chakar, F.S. and A.J. Ragauskas, Review of current and future softwood kraft lignin process chemistry. Industrial Crops and Products, 2004. 20(2): p. 131-141.

9.             Landin, M., et al., Effect of country of origin on the properties of microcrystalline cellulose. Int. J. Pharm., 1993. 91(2-3): p. 123-31.

10.          Landin, M., et al., Effect of batch variation and source of pulp on the properties of microcrystalline cellulose. Int. J. Pharm., 1993. 91(2-3): p. 133-41.

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