Cellulose, Microcrystallin

1 Nonproprietary Names Table I: Uses of microcrystalline cellulose.

BP: Microcrystalline Cellulose Concentration (%)
Use
ỊP: Microcrystalline Cellulose
Adsorbent 20-90
PhEur: Cellulose, Microcrystalline 5-20
Antiadherent
USP-NF: Microcrystalline Cellulose Capsule binder/diluent 20-90
Tablet disintegrant 5-15
Tablet binder/diluent 20-90_______
2 Synonyms
Avicel PH; Cellets; Celex; cellulose gel; cellulosum microcristalli-
num; Celpbere; Ceolus KG; crystalline cellulose; Cyclocel; E460; 9 Pharmacopeial Specifications
Emcocel; Fibrocel; Grinsted MCC; MCC Sanaq; Microcel; Pbar- The pharmacopeial specifications for microcrystalhne cellulose
macel; Tabulose; Vivapur. have undergone harmonization of many attributes for JP, PhEur,
and USP-NF.
3 Chemical Name and CAS Registry Number See Table II. See also Section 18.
Cellulose [9004-34-6] Table II! Pharmacopeial specifications for microcrystalline cellulose.

4 Empirical Formula and Molecular Weight Test JP XVII PhEur 9.2 USP 40-
NF 35 SI
(C6H10O5)„ «36 000 where ft « 220.
Identification + + 4-
Characters^ + +
pH 5.0-7.5 5.0-7.5 5.Q-7.5
Bulk density + 4-
Loss on drying <7.0% <7.0% <7.0%
Residue on ignition <0.1% <0.1%
Conductivity + +
Sulfated asn <0.1 %
Ether-soluble substances <0.05% <0.05% <0.05%
Water-soluble substances + <0.25% <0.25%
Heavy metals^ < 10 ppm < 1 0 ppm
Microbial limits^
Aerobic < 1o2 cfu/g < 10^ cfu/g < 1 o2 cfu/g
Molds and yeasts < 1 o2 cfu/g < 1 o2 cfu/g < 1 o2 cfu/g
Solubility 4-
Particle size distribution + +

(a) This test has not been fully harmonized at the time of publication.

SEM 1: Excipient: microcrystalline cellulose; manufacturer: JRS Pharma

LP; lot no.: 98ÓÓ2; magnification: lOOx.

6 Functional Category
Adsorbent; direct compression excipient; suspending agent; tablet
and capsule diluent.

7 Applications in Pharmaceutical Formulation or

Technology
Microcrystalline cellulose is widely used in pharmaceuticals,
primarily as a binder/diluent in oral tablet and capsule formulations
where it is used in dry-granulation, wet-granulation, and direct-
compression processes?1-61 In addition to its use as a binder/diluent,
microcrystalline cellulose may also reduce friction during tablet
ejection(7) and facilitate tablet disintegration.(8) Microcrystalline
cellulose has been used with nanoparticles and nanogels for
modified drug release?9,10) Certain spherical-shaped grades may
be used for drug layering?111 See Table I for some of the uses and
concentrations of microcrystalline cellulose.

8 Description
Microcrystalline cellulose is a purified, partially depolymerized
cellulose that occurs as a white, odorless, tasteless powder
composed of porous particles.

194
 Cel lulose, Microcrystalline 195
SEM 2: Excipient, microcrystalline cellulose (Avicel PH-101); SEM 4: Excipient: microcrystalline cellulose (Avicel PH-105);
manufacturer: FMC Biopolymer; magnification: 200x; voltage: 3 kv. manufacturer: FMC Biopolymer; magnification: 500x; voltage: 3 kv.

SEM 3: Excipient: microcrystalline cellulose (Avicel PH-102);

manufacturer: FMC Biopolymer; magnification: 200x; voltage: 3 kv. SEM 5: Excipient: microcrystalline cellulose (Avicel PH-200);
manufacturer: FMC Biopolymer; magnification: 200x; voltage: 3 kv.

SEM 6: Excipient: microcrystalline cellulose (Avicel PH-302);

10 Typical Properties manufacturer: FMC Biopolymer; magnification: 200x; voltage: 3 kv.
Angle of repose
49 for Ceolus KG;
34.4 for Emcocel 90M.{ỉ2)
Density (bulk)
0.337 g/cm3;
0.32 g/cm3 for Avicel PH-101;(iy>
0.80 ± 0.05g/cm3 for Cellets 100, 200, 350, 500, 700, 1000;
0.29 g/cm3 for Emcocel 90M;(12)
10 *
0.26-0.31 g/cn? for MCC Sanaq 101;
0.28-0.33 g/cm3 for MCC Sanaq 102;
0.29-0.36 g/cm3 for MCC Sanaq 200;
0.34-0.45 g/cm3 for MCC Sanaq 301;
0.35-0.46 g/cm3 for MCC Sanaq 302;
0.13-0.23 g/cm3 for MCC Sanaq ƯL-002;
0.29 g/cm3 for Vivapur 101.
Density (tapped)
0.478 g/cm 3; Moisture content Typically less than 5% w/w. However, different
grades may contain varying amounts of water. Microcrystalline
0.45 g/cm3 *for Avicel PH-101;
cellulose is hygroscopic.(16)
0.35g/cm3 for Emcocel 90M.(i2) See Table III.
Density (true) Particle size distribution Different grades may have a different
1.512-1.668 g/cm3; nominal mean particle size; see Table III.
1.420-1.460 g/cm3 for Avicel PH-102 Solubility Slightly soluble in 5% w/v sodium hydroxide solution;
Flowability 1.41 g/s for Emcocel 90M.(i2}Avicel PH-102 exhibits practically insoluble in water, dilute acids, and most organic
flow properties adequate for high-speed tableting/15) solvents.
 196 Cellulose, Microcrystalline

Specific surface area

1.06-1.12 m2/g for Avicel PH-101;
1.21-1.30 m2/g for Avicel PH-102;
0.78-1.18 m2/g for Avicel PH-200.
Spectroscopy
IR spectrum see Figure 1.
NIR spectrum see Figure 2.
Raman spectrum see Figure 3.

11 Stability and Storage Conditions

Microcrystalline cellulose is stable, physically and chemically, in
ambient conditions, charring at 260-270 c. The bulk material is
hygroscopic and should be stored in well-closed containers in a
cool, dry place.
Figure lĩ Infrared spectrum of microcrystalline cellulose measured by
12 Incompatibilities diffuse reflectance. Adapted with permission of Informa Healthcare.
Microcrystalline cellulose is incompatible with strong oxidizing
agents.

13 Method of Manufacture
Microcrystalline cellulose is typically manufactured by controlled
hydrolysis with dilute mineral acid solutions of oc-cellulose, obtained
as a pulp from fibrous plant materials. Following hydrolysis, the
hydrocellulose is washed with water and filtered. The aqueous
slurry is then spray-dried to form a dry powder.

14 Safety
Microcrystalline cellulose is widely used in oral pharmaceutical
formulations and food products, and is generally regarded as a 1100 1300 1500 1700 1900 2100 2300 2500
relatively nontoxic and nonirritant material.
Microcrystalline cellulose is not absorbed systemically following Wavelength/nm
oral administration and thus has little toxic potential. Consumption
of large quantities of cellulose may have a laxative effect, although Figure 2: Near-infrared spectrum of microcrystalline cellulose measured
this is unlikely to be a problem when cellulose is used as an excipient by reflectance.
in pharmaceutical formulations.
Deliberate abuse of formulations containing cellulose, either by
inhalation or by injection, has resulted in the formation of cellulose
granulomas.(17)
LD50 (rat, oral): 3.16 g/kg(18)
LD50 (rat, IP): 3.16 g/kg(18)
LD50 (rat, skin): 2.0 g/kg(18)

15 Handling Precautions
Observe normal precautions appropriate to the circumstances and
quantity of material handled. Microcrystalline cellulose may be
irritating to the eyes. Gloves, eye protection, and a dust mask are
recommended. In the UK, the workplace exposure limits for
cellulose have been set at 10mg/m3 long-term (8-hour TWA) for Wavenumbers/cm 1
total inhalable dust and 4 mg/n? for respirable dust; the short-term
limit for total inhalable dust has been set at 20mg/m3.(19) Figure 3: Raman spectrum of microcrystalline cellulose measured in the
1 80 reflectance mode. Adapted with permission of Informa Healthcare.
16 Regulatory Status
Although not GRAS listed, the Select Committee on GRAS 17 Related Substances
Substances (SCOGS) regard the current and future use of Microcrystalline cellulose and carboxymethylcellulose sodium,
Microcrystalline Cellulose as non-hazardous.(2()) Included in the coprocessed; powdered cellulose; silicified microcrystalline cellu­
FDA Inactive Ingredients Database (inhalations; injections; oral lose.
capsules, powders, granules, suspensions, syrups, and tablets;
topical and vaginal preparations; transdermal patches.) Included
in nonparenteral medicines licensed in the UK. Included in the 18 Comments
Canadian Natural Health Products Ingredients Database. Accepted Microcrystalline cellulose has undergone harmonization of many
for use as a food additive in Europe. attributes for JP, PhEur, and USP-NF by the Pharmacopeial
 Cel ulose, Microcrystalline 197

Table III! Properties of selected commercially available grades of particle-size grades generally provide better flow properties in
microcrystalline cellulose. pharmaceutical machinery. Low-moisture grades are used with
moisture-sensitive materials. Higher-density grades have improved
Grade Nominal Particle size analysis Moisture flowability.
mean content (%) Microcrystalline cellulose is generally regarded as a plastic
particle size Mesh size Amount material, with its plasticity affected by moisture content. The
(pm)
retained (%) tabletability of raw powders and granulated powders depends on
Avicel PH-101 ,o> 50 particle size, porosity, and moisture content.(33_36) Although
Ó0 <1.0 <5.0
microcrystalline cellulose is widely recognized to be one of the
200 <30.0
Avicel PH-102™ 100 Ó0
most important excipients for the large-scale manufacture of tablets
<8.0 <5.0
200
by direct compression, there is an inevitable variability in its
>45.0
Avicel PH-103|a| 50 tableting properties/3 1 Novel tableting excipients have been
Ó0 <1.0 <3.0
200
developed, which may be more advantageous with regard to their
<30.0
Avicel PH-105(a| 20 400
specific surface area and other tableting properties.i38)
<1.0 <5.0
Avicel PH-1 12(a| 100 Ó0 <8.0 <1.5
Several coprocessed mixtures of microcrystalline cellulose with
Avicel PH-1 13(a) 50 Ó0 <1.0 <1.5
other excipients such as dibasic calcium phosphate, mannitol, and
200 <30.0
guar gum are commercially available; and used, for example, in
Avicel PH-200™ 180 Ó0 >10.0 <5.0
roller compaction, chewable tablet formation and direct compres­
100 >50.0 sion. For coprocessed mixtures with carboxymethylcellulose
Avicel PH-200 LM™ 180 Ó0 >10.0 <1.5
sodiumsee Section 17.
100 >50.0 Celphere (Asahi Kasei Corporation) is a pure spheronized
Avicel PH-301(a| 50 Ó0 <1.0 <5.0 microcrystalline cellulose available in several different particle size
200 <30.0 ranges. Balocel Sanaq (Pharmatrans Sanaq AG) is an excipient used
Avicel PH-302™ 100 Ó0 <8.0 <5.0 mainly in the production of pellets and granulates in direct
200 >45.0 tableting, which contains lactose, microcrystalline cellulose, and
Ceolus KG-802™ 50 Ó0 <0.5 <0.0 sodium carboxymethylcellulose.
200 <30.0 According to PhEur 9.2, microcrystalline cellulose has certain
Emcocel 50M^ 50 Ó0 <0.25 <5.0 functionality related characteristics that are recognized as being
200 <30.0 relevant control parameters for one or more functions of the
Emcocel 90M^ 91 Ó0 <8.0 <5.0 substance when used as an excipient. Non-mandatory testing
200 >45.0 procedures have been described for particle size distribution (2.9.31
MCC Sanaq 101^ 50 Ó0 <1.0 <6.0 or 2.9.38) and powder flow (2.9.36).
200 <30.0 Microcrystalline cellulose is also used in cosmetics and food
MCC Sanaq 102^ 100 Ó0 <8.0 <0.0 products.
200 >45.0 A specification for microcrystalline cellulose is contained in the
MCC Sanaq 200^ 180 Ó0 >10.0 <6.0 Food Chemicals Codex (FCC).(39)
100 >50.0 The PubChem Compound ID (CID) for microcrystalline cellu­
MCC Sanaq 30 J 50 Ó0 <1.0 <6.0 lose is 14055602.
200 >30.0
MCC Sanaq 302^ 100 Ó0 <8.0 <6.0 19 Specific References
200 >45.0
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20 General References
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(accessed 27 August 2014).
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21 Authors
ME Quinn, cc Sun.
22 Date of Revision
4 May 2017.