Vol 2, Issue 3, 2020 (89-96)

http://journal.unpad.ac.id/idjp

*Corresponding author,

e-mail : nagina17001@mail.unpad.ac.id (N. Belali)

https://doi.org/10.24198/idjp.v2i3.30857

Microcrystalline Cellulose isolated from Rami (Boehmeria nivea L. Gaud) used as a

disintegrant in Dimenhydrinate tablets

Nagina Belali

1,2

, Anis Y. Chaerunisaa

, Taofik Rusdiana

Department. of Pharmaceutics, Faculty of Pharmacy, Kabul University, Jamal mena, 1006, Kabul,

Afghanistan

1,2

Department. of Pharmaceutics, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Jatinangor

KM 21.5 Bandung-Sumedang, 45363

Received : 3 Des 2020, Revised : 8 Des 2020, Accepted : 17 Des 2020, Published : 27 Dec 2020

ABSTRACT

Microcrystalline cellulose was isolated from rami (Boehmeria Nivea L. Gaud), and applied

as disintegrant in tablets of dimenhydrinate, made by direct compression and wet

granulation. The aim of this study is to produce dimenhydrinate tablets with

Microcrystalline Cellulose Rami (MCC Rami) isolated from Rami (Boehmeria Nivea L.

Gaud), as a disintegrant and assess the effect of MCC Rami and Granulation technique on

physical properties of drug such as, disintegration time, drug release and dissolution.

Formulations of dimenhydrinate 100mg tablets were prepared with a combination of

mannitol and lactose as a filler and MCC Rami as disintegrant in a concentration of 10-

20%. The formulas were directly compressed or were compressed into tablets after wet

granulation. The mechanical properties, drug release, physical properties and effects of

process parameters, methods of applying disintegrant in tablet formulas were examined. A

significant difference in disintegration time of tablets that were produced by direct

compression and wet granulation was seen, that can be attributed to the porous structure of

granules that enhanced fast disintegration, which had eventually improved dissolution and

drug release. F1 and F2 with MCC Rami and physical mixture of MCC Rami with

crosspovidone as a disintegrant that were directly compressed disintegrated in 79 and 72

seconds respectively thats not a significant difference, however when MCC was applied in

an intragranular way its disintegration time is 67 seconds. The results showed that the

method of disintegrant application and press of tableting has a significant effect on drug

release and dissolution.

Keywords: Microcrystalline Cellulose, wet granulation, disintegrant, Boehmeria Nivea L.

Gaud.

1. Introduction

Microcrystalline cellulose (MCC) is so

versatile that has a widespread application in

many fields from food to pharmaceuticals.

MCC is becoming more popular now because

of its increasing number of alternatives made

by co-processing it or either making bio-

composites of MCC (1). In pharmaceutical

department it has been considered for last fifty

years as diluent in direct compression (DC) of

tablets, its compactibility, tabletability, easy

supply, inertness, compatibility and availability

makes it popular. MCC is a partially

depolymerized cellulose that is achieved by

acid application on cellulose obtained from

fibrous plants and wood (2). There are a

number of studies that have prepared MCC

from different raw materials but all of them

have used the same method of acidic

hydrolysis; such as Dutta Kalita et al have

extracted microcrystalline cellulose from

fodder grass that is very cheap and

environmental friendly and has applied as a

drug delivery vehicle for isoniazid (3). Kale et

N. Belali et al / Indo J Pharm 3 (2020) 89-96

al also reported ectraction of microcrystalline

cellulose from cotton silver (4).

MCC is mostly applied as a filler in tableting

due to its good binding properties it is a

preferred filler for direct compression,

moreover it has self-disintegrating properties

although it doesn’t take away the need of using

a disintegrant but it can promote disintegration

(5). Therefore, the disintegrating properties of

MCC has been neglected that we aim to assess

in current study. However, studies have shown

that combining MCC with superdisintegrants

have complementary effects on enhancing

disintegration (6). MCC has high porosity that

gives a surface area of 90-95% approximately

(7), that would promote disintegration by

swelling and the penetration of water into the

hydrophilic tablet matrix with help of capillary

action of the pores (8).

Disintegration properties of tablet can be

improved by different process methods, one of

which is wet granulation as it creates granules

that are porous and will help in water uptake

that will improve disintegration of tablets, that

was studied by Ramana et al in producing

pioglitazone fast disintegrating tablets (9).

Despite of the increased focus and in the area

of targeted drug delivery system in recent

years, tablet dosage forms that are intended to

be swallowed whole, disintegrate, and release

their medicaments rapidly in the

gastrointestinal tract still remain the

formulation of choice from both a

manufacturing as well as a patient acceptability

point of view (10). Thus, a drug given in the

form of a tablet must undergo dissolution

before being absorbed and eventually

transported into systemic circulation. For most

of the tablet dosage forms, disintegration

precedes drug dissolution. MCC is economical

and is used in large batches of tablet production

by DC, it is one of the best tablet diluents, and

thus we try to explore its disintegration

properties as well that will eventually promote

better drug dissolution.

2. Method

2.1 Material and Instrument

Dimenhydrinate (Central Laboratory,

UNPAD), Lactose (Formulasi dan Teknologi

Farmasetika LAB), Mannitol, Microcrystalline

Cellulose Rami (MCC Rami was prepared in

Central Lab UNPAD), Crosspovidone (JRS

Pharma), Tapped density tester (Erweka SVM

221) Rotary Tableting Machine, Dissolution

Tester (Zotax), Disintegration tester

(Metlertoledo), Hardness Tester

(Metlertoledo), Friability Tester (Erweka).

2.2 Preformulation parameter study

Physical properties of Isolated MCC from

Rami and its prepared co-processed

disintegrant and formulation of tablets were

studied by evaluating Angle of repose, Tapped

and bulk density, Hausner’s Ratio and Carr’s

Index by procedures given below (11);

2.3 Angle of repose

Flowing properties of Isolated MCC from Rami

and its prepared co-processed disintegrant were

evaluated with help of Flow Rate analyzer

Metler Toledo. The sample was poured through

the funnel until the apex of the conical pile

touched the tip of the funnel. The angle of

repose was calculated using the formula tan α =

H/R, where α is the angle of repose and R is the

radius of the conical pile.

Table 1. Angle of repose and flow

properties of powder

Flow property

Angle of Repose

(Degrees)

Excellent

25-30

Good

31-35

Fair

36-40

Passable

41-45

Poor

46-55

Very Poor

56-65

Very, very Poor

>66

2.4 Determination of tapped and bulk

density, Hausner’s Ratio and Carr’s

index

The powder property tester was used to

determine the bulk (ρb) and tapped (ρta)

densities for the compressibility studies.

Compressiblity was reflected by Hausner ratio.

Bulk density was measured by pouring samples

through a vibrating metal funnel into a

measuring cylinder until it was full. The

N. Belali et al / Indo J Pharm 3 (2020) 89-96

volume of the cylinder was exactly 100 cm

and

pre-weighted as m

ρta = m

- m

/100 (1)

After the excessive powder was scraped off, the

weight of the cylinder containing powder was

recorded as m1. The bulk density was

calculated by Eq.1 ρb ¼ m1 m

(1)Tap density

was obtained by pouring more samples into the

cylinder until an appropriate height with aid of

a glass sleeve. Tapping was carried out for 5

min. After the excessive powder was scraped

off, the weight of the cylinder containing

sample was recorded as m2. The tap density

and Hausner ratio were calculated by Eqs.1 and

2, respectively (12).

ρb = m

- m

/100 (2)

Carr’s ‘percent compressibility and the

Hausner ratio were calculated using the

equation Dt – Db/Dt x 100 and t/ b respectively.

t and b are respectively the tapped and bulk

densities (13).

Table 2. Carr’s Index value

Carr’s Index (%)

Type of flow

5-15

Excellent

12-18

Good

18-23

Fair to passable

23-35

Poor

35-38

Very poor

>40

Extremely poor

2.5 Hausner ratio

Hausner ratio is an indirect index of ease of

powder flow. It is calculated by the following

formula

Hausner ratio = Dt/Db

Where, Dt is the tapped density, and Db is the

bulk volume. The inter relationship between

angle of repose and flow properties of powders

is shown in table 3.

2.6 Preparation of dimenhydrinate

Tablets

Tablets containing 100 mg of dimenhydrinate

were prepared by direct compression and wet

granulation method and the various formulas

used in the study are shown in the table 4. For

direct compression the required amounts were

weighed and mixed well and directly

compressed. For wet granulation the drug and

diluent, disintegrant (and superdisintegrant) in

required quantities and properly mixed and

granules were prepared by using ethanol as a

binder solution (14). The cohesive mass was

passed through mesh number 20 and dried at

temperature of 40˚C in oven. The dried mass

was sieved. Then lubricants and glidants

(Magnesium stearate, and talc) were added

mixed well and then compressed into tablets.

The tablets were prepared by rotary die

compression machine (15).

2.7 Evaluation of prepared tablets (post-

compression parameters)

2.7.1 Weight variation and Tablet Hardness

and thickness

The formulated tablets were tested for weight

uniformity, hardness and thickness. For this 20

tablets were weighed individually in metller

toledo chemical balance. Thickness and

hardness of tablets was measured using Metller

Toledo hardness tester. The mean and Standard

Deviation of hardness values were calculated

(16).

2.7.2 Friability

Friability of the tablets was determined by

using Metller Toledo friabilator. The weight of

20 tablets (initial weight) was subjected to

friabilator at 25 revolutions per 4 min. Tablets

were then dedusted, reweighed (final weight)

and percentage loss was calculated (17).

Friability is obtained by the following formula:

%friability = Initial weight – Final weight/

Initial weight *100

Table 3. Hausner ratio

Hausner ratio

Type of flow

<1.25

Good

1.25-1.5

Moderate

>1.5

Poor

N. Belali et al / Indo J Pharm 3 (2020) 89-96

2.7.3 Wetting time and Water Absorption

Ratio

A double folded tissue paper was placed in a

Petri dish. 10 mL of water containing a water-

soluble dye was added to the Petri dish. A tablet

(pre-weighed) was carefully placed on the

surface of tissue paper. The time required for

water to reach the upper surface of the tablet

was noted as the wetting time. The wetted tablet

was then weighed and the water absorption

ratio (R) was determined by using the equation:

R = (Wb-Wa) / Wb *100 (3)

Where Wa and Wb are the weights of tablet

before (dry weight) and after water absorption

(wet weight) respectively (18).

Table 4: Formulation of Dimenhydrinate Tablets

Ingredients (mg)

***

Dimenhydrinate

100

Mannitol

100

PVP

MCC Rami

Crosspovidone

Talc

Mg stearate

Flavorant

Lactose

q.s to 600mg

Directly compressed,

MCC Rami with Crosspovidone applied intragranularly in Tablets,

***

Physical mixture of MCC Rami with Crosspovidone directly compressed.

2.7.4 In vitro Disintegration Study

The disintegration time of tablet was

determined using disintegration apparatus in

distilled water as disintegration medium

maintained at 37˚C. When all the six tablets are

completely disintegrated, the time was noted

(19).

2.7.5 Determination of maximum

absorption wavelength of

Dimenhydrinate

Maximum absorption wavelength (λ max) for

dimenhydrinate, a 10µg/ml solution of

dimenhydrinate was prepared in Simulated

Gastric Fluids later its absorbance would be

determined by UV spectrophotometer (16).

2.7.6 Calibration Curve

Calibration Curve of dimenhydrinate was

prepared in Simulated Gastric Fluids

(Hydrochloric acid buffer pH 1.2) with

concentrations from 10µg/ml until 30µg/ml.

After recording λ max calibration curve was

drawn in Excel program (20).

2.7.7 In vitro Dissolution Study

Dissolution studies were conducted to

determine the release pattern of the drug from

the product. Dissolution test for

dimenhydrinate tablet was carried out as per

USP method for dissolution test for tablets and

capsules using apparatus II (paddle type).

Dissolution medium used was 900 mL of SGF,

agitation speed at 50 rpm at 37±0.5˚C. An

aliquot sample of 5 mL was withdrawn at

different time periods and replaced with fresh

medium. These samples were filtered and

diluted suitably. Absorbance of the resulting

solution was measured at 267 nm. Percentage

cumulative drug release was calculated (21).

3. Results

3.1 Flow Properties

Microcrystalline cellulose was isolated from

fiber of Boehmeria Nivea L. Gaud called Rami

in Indonesia. MCC Rami used was available in

Faculty of Pharmacy, Universitas Padjadjaran

that was isolated and characterized before (22),

since flow properties are of significance in

uniformity of tablets mass, we further evaluated

the flow properties of MCC Rami and

Formulations intended to be directly

compressed in to tablets, the results are given in

table 5. Results revealed that F1 and F2 have

angle of repose 36 and 30, Carr’s Index 37.7

and 35.8, Hausner’s ratio 1.41 and 1.55 that

shows they doesn’t have good flow properties

that come in range of poor to moderate,

therefore in direct compression there were

some problems thus we intend to granulate the

formulas first and then compress them into

tablets.

Table 5: Flow Properties (n=3)

Parameters

MCCRami

6.4%

Bulk Density

0.4g/cm

0.52g/cm

0.377g/cm

Tapped Density

0.5g/cm

0.83g/cm

0.588g/cm

Hausner Ratio

1.25

1.41

1.55

Carr’s Index

37.7

35.8

Angle of Repose

3.2 Evaluation of Tablets

3.2.1 Weight variation and Hardness

Results of tablets weight uniformity, thickness

and hardness are in acceptable range.

3.2.2 Wetting time and water absorption

ratio

They show the capacity of disintegrant that how

much water it can take into tablet, where water

absorption ratio was 17% for tablets with MCC

Rami as a disintegrant, and increased to 25%

when MCC Rami was applied intragranularly

and further increased to 27% when physical

mixture of MCC Rami is used with

Crosspovidone. Wetting time results were the

same it decreased from MCC Rami to PM of

Crosspovidone and MCC Rami.

3.2.3 Disintegration Time

F1 and F2 with MCC Rami as a disintegrant

have disintegration time of 79 and 72 seconds

respectively that is considered a very good

disintegration time, as shown in table 6.

Table 6: Tablet Characterization (n=3)

Parameters

***

Weight variation(mg)

595±3

611±3

598±8.6

Thickness(mm)

5±0.03

5.10±0.03

Hardness(N)

45.50±8

65.70±4

44.85±7

Diameter (mm)

13±0.01

13.02±0.02

Friability%

13%

0.7%

Disintegration(s)

79 ±24

72s ±11

67s ±13

Waterabsorption ratio%

17%

25%

24%

Wetting time (s)

79s

72s

78s

Directly compressed,

Physical mixture of MCC Rami with Crosspovidone directly compressed,

***

MCC Rami with Crosspovidone applied intragranularly in Tablet

3.2.4 In-Vitro Dissolution Test Results

Maximum absorption wavelength of

dimenhydrinate was determined in SGF, that

was 267nm for dimenhydrinate. Standard

calibration curve was prepared in the same

media that is shown in figure 1. As shown in

figure 2, 80% of the drug is released in 10

minutes.

Microcrystalline cellulose shows promising

properties of disintegration. According to USP

and BP for conventional tablets acceptable

disintegration time is 15 minutes and for

dispersible tablets is less than 3 minutes. Since

disintegration time of dimenhydrinate tablet

with MCC Rami as a disintegrant is 79 seconds

that’s even less than 3 minutes for dispersible

tablets, it reveals good disintegration properties

of MCC Rami and it can be used even in

dispersible tablets. In order to compare the

disintegration effect of MCC with

crosspovidone in F3 a physical mixture of both

was applied in a ratio of 10:1 respectively.

Figure 1: Calibration curve of

Dimenhydrinate in Gastric media

Figure 2: Cumulative drug release

Disscusion

On the basis of results shown in table 6

disintegration time decreased that is attributed

to addition of crosspovidone that increases

water uptake, swells and tends to disintegrate

fast. This result is in consistence with work

done by Setty as they also concluded that

disintegration time was decreased if tablets

were produced by wet granulation due to

having porous structure that was further

decreased by using superdisintegrant (23).

Disintegration time for tablet with

crosspovidone in Setty et al was 12s because

they had used 25mg crosspovidone per tablet

which is quite high quantity in comparison to

our study where crosspovidone is just 2% of

formulation 3mg and disintegration time is 67s

that is a good disintegration time for

conventional tablets. In the same research

article one formula was produced with

microcrystalline cellulose 78mg/tablet as a

diluent with a mixture of mannitol that is quite

similar to formualtions used in our study

without any superdisintegrant, and

disintegration time was 3minutes, and hence if

we compare the disintegration of MCC Rami

with Microcrystalline Cellulose used in study

done by Setty et al shows much better

properties as a disintegrant.

Another study by Ramana et al, reported

formulation of pioglitazone fast disintegrating

tablets prepared by direct compression and wet

granulation, where one of the superdisintegrant

applied was crosspovidone that were similar to

our study, and formula with 6mg of

crosspovidone per tablet that was directly

compressed had disintegration time of

69seconds less than formulas done by wet

granulation that is 45 seconds (9). So it can be

seen that wet granulation can have significant

effects on tablet disintegration.

Figure 3: Disintegration time

According to USP tolerance for

dimenhydrinate dissolution test results is not

less than 75% of the labeled amount is

dissolved in 45 minutes and in the figure we can

see that 80% of drug is release in course of

10minutes, thus we can conclude that because

of low disintegration time drug dissolution can

be enhanced that would resultantly increase the

bioavailability of drug (10).

4. Conclusion

y = 0,0254x + 0,0076

R² = 0,9926

0,5

0 10 20 30 40

ABS

Concentration µg/ml

cal curve dimenhydrinate

0,00%

20,00%

40,00%

60,00%

80,00%

100,00%

120,00%

140,00%

-20 0 20 40 60 80

% drug release

Time (minutes)

100

F1 (DC) F2 (PM) F3 (IG)

Disintegration time

Formulas

It is concluded from the current study that

Microcrystalline Cellulose Rami (MCC Rami)

has appreciable disintegrant properties that can

be even applied in dispersible tablets due to its

fast disintegration properties that happens in

less than one and half minute. Moreover, wet

granulation is a good technique to overcome

preformulation problems and can contribute to

better disintegration due to porous structure of

granules that will eventually enhance the

dissolution and bioavailability of drug, as

shown in the results where disintegration time

of F3 is 78s, although for immediate release

tablets disintegration time can be up to 15min.

Further research is needed to assess the

disintegration properties of MCC Rami.

References

1. Thoorens G, Krier F, Leclercq B, Carlin

B, Evrard B. Microcrystalline cellulose ,

a direct compression binder in a quality

by design environment — A review.

Elsevier BV. 2014;

2. Thoorens G, Krier F, Rozet E, Carlin B,

Evrard B. Understanding the impact of

microcrystalline cellulose

physicochemical properties on

tabletability. Int J Pharm. 2015;490(1–

2):47–54.

3. Dutta R, Nath Y, Ochubiojo ME, Kumar

A. Colloids and Surfaces B :

Biointerfaces Extraction and

characterization of microcrystalline

cellulose from fodder grass ; Setaria

glauca ( L ) P . Beauv , and its potential

as a drug delivery vehicle for isoniazid ,

a first line antituberculosis drug. Colloids

Surfaces B Biointerfaces. 2013;108:85–

4. Kale RD, Shobha P, Vikrant B.

Extraction of Microcrystalline Cellulose

from Cotton Sliver and Its Comparison

with Commercial Microcrystalline

Cellulose. J Polym Environ. 2017;0(0):0.

5. Pate NK, Upadhyay AH, Bergum JS,

Reier E. An evaluation of

microcrystalline cellulose and lactose

excipients using an instrumented single

station tablet press. 1994;5173(94).

6. Mostafa, H.F., Ibrahim, M.A., Sakr A.

Development and optimization of

dextromethorphan hydrobromide oral

disintegrating tablets: effect of

formulation and process variables. Pharm

Dev Technol. 2013;(18):454–463.

7. Development D, Pharmacy I.

COMPARATIVE TABLETING

PROPERTIES OF SIXTEEN.

1987;13:1847–75.

8. Gamble JF, Chiu W, Tobyn M.

Investigation into the impact of sub-

populations of agglomerates on the

particle size distribution and flow

properties of conventional

microcrystalline cellulose grades.

2011;16(May 2010):542–8.

9. Ramana B V, Murthy TEGK.

International Journal of Medicine and

Open Access Formulation and

Comparative Evaluation of Pioglitazone

Fast Disintegrating Tablets Prepared by

Dry and Wet Granulation Techniques.

2016;4(5):252–61.

10. Bilac H, Guler E. Studies on controlled

release dimenhydrinate from matrix

tablet formulations. 1999;

11. Singh V, Kumar L, Meel RK. Research

Article Formulation and Development of

Sustained Release Matrix Tablet of

Ranolazine. 2014;3(11):22–32.

12. Wang S, Li J, Lin X, Feng Y, Kou X,

Babu S, et al. Novel coprocessed

excipients composed of lactose, HPMC,

and PVPP for tableting and its

application. Int J Pharm. 2015;486(1–

2):370–9.

13. Ogaji. Film coating potential of okra gum

using paracetamol tablets as a model

drug. Asian J Pharm. 2010;4(2):130.

14. Chowdary KPR, Enturi V, Pallavi T V.

Formulation Development of Etoricoxib

Tablets by Wet Granulation and Direct

Compression Methods Employing Starch

Phosphate- A New Modified Starch.

2011;3(6):163–72.

15. Jaya S, K.P.R. C, Rao PR. Effect of

Binders on the Dissolution Rate and

Dissolution Efficiency of Ritonavir

Tablets. 2012;2(Iv):109–13.

16. Ofdimenhydrinate E, Tablets MD.

FORMULATION AND EVALUATION

OFDIMENHYDRINATE.

2015;4(9):1123–34.

17. Evaluation of Coprocessed Disintegrants

Produced From Tapioca Starch and

Mannitol in Orally Disintegrating

Paraceta .... 2014;(September).

18. Shirsand SB, Para MS, Ramani RG,

Swamy P V., Kumar DN, Rampure M V.

Novel co-processed superdisintegrants in

the design of fast dissolving tablets. Int J

PharmTech Res. 2010;2(1):222–7.

19. Swamy et al. Design and characterization

of oral dispersible tablets of enalapril

maleate using a co-processed excipient. J

Appl Pharm Sci. 2012;2(11):40–9.

20. Pezeshki SS, Jafariazar Z, Mortazavi SA.

Formulation and physicochemical

evaluation of dimenhydrinate Oral Fast

Dissolving Film . 2014;20(Supp 1):2014.

21. Shah N, Dalvadi H, Naik P, Desai A,

Patel N. Formulation and Evaluation of

Immediate Release Tablet of Cinnarizine

and Dimenhydrinate. Int J Pharma Sci

Res. 2016;7(December):185–9.

22. Nawangsari D, Chaerunisaa AY,

Abdassah M, Sriwidodo S, Rusdiana T,

Apriyanti L. Isolation and

Physicochemical Characterization of

Microcristalline Cellulose from Ramie

(Boehmeria nivea L. Gaud) Based on

Pharmaceutical Grade Quality. Indones J

Pharm Sci Technol J Homepage.

2018;5(2):55–61.

23. Setty CM, Radhika M, Gupta VRM,

Reddy MVR, Jithan A V. Effect of Tablet

Processing and Formulation Factors on

Disintegration and Dissolution of

Aceclofenac Tablets Effect of Tablet

Processing and Formulation Factors on

Disintegration and Dissolution of

Aceclofenac Tablets ABSTRACT :

2011;(January).