Composition Ratio of Lactose and Corn Starch in Granule Capsule

Formulation of 70% Ethanol Extract Justicia gendarussa leaves as

Male Contraceptive

Bambang Prajogo EW

, Esti Hendradi

,and Pramudita Riwanti

Pharmacognosy Department, Faculty of Pharmacy, Airlangga University, Surabaya

Chemical Pharmacy Department, Faculty of Pharmacy, Airlangga University, Surabaya

Keywords: Justicia gendarussa, lactose, corn starch

Abstract: The objective of this study were to make a good physical properties of Justicia gendarussa granules with

lactose and corn starch as filler. Optimizations were made into 3 formulas. The difference of each formula

was in the ratio of corn starch and lactose. Formula 1 used ratio 3:7 for corn starch and lactose, Formula 2

used ratio 1:1 for lactose and corn starch, Formula 3 used ratio 7:3 for corn starch and lactose. Physical

evaluation was held to evaluate and choose the best granule like flowability, fines content, angle of repose,

moisture content, compressibility. The result for granules optimization, flowability formula 1 was 3,29 ±

1,08 g/s, formula 2 was 6,04 ± 1,80 g/s, formula 3 was 6,48 ± 1,32 g/s. Angle of repose for F1,2 and 3 were

30,54 ± 1,14

, 29,98 ± 0,34

and 26,98 ± 0,00

. Compressibilty index were 12,00% , 10,00% and 11,99%.

Moisture content 1,82%, 2,08% and 2,75%. Fines content were above 20%. From the evaluation, F2 was

selected as the best formula.

1 INTRODUCTION

Justicia gendarussa is a tropical plant which grow

in tropic land including Indonesia. This plant have

been used by society of Papua as male contraceptive

(Prajogo, 2002). Major components from genus

Justicia are alkaloid, lignan, flavonoid and

terpenoid. Gendarussa leaves also contain tannin,

kalium, volatile oil.calcium oxalate and also alkaloid

(justicina) which is toxic (Chakravarty et al., 1982).

Alkaloid have been isolated from J.gendarussa

leaves are 2-amino benzyl alcohol; 2-amino-o-metyl

benzyl alcohol; 2-(2’-amino-benzilamino) benzil

alcohol; 2-(2’amino-benzil)-o-metil-benzil ackohol

(Fig.1) (Carstensen & Rhodes, 2000).

Figure 1: Chemical structure aromatic amin substituted isolated from J.gendarussa leaves.

Composition Ratio of Lactose and Corn Starch in Granule Capsule Formulation of 70 .

DOI: 10.5220/0008359601830189

In Proceedings of BROMO Conference (BROMO 2018), pages 183-189

ISBN: 978-989-758-347-6

183

Flavonoids from Justicia gendarussa Burm.

f. are 6,8-di-C-α-L-arabinosil-4', 5,7 trihydroxy-

flavon or 6,8-di-C-α-Larabinosilapigenin and this

compound called gendarusin A, C-α-L-

arabinopiranosil-4 ', 5,7 - trihydroxy-8-C-β-D-

silopiranosilflavone or 6-C-α-L-arabinosil- 8-C-β-D-

silosilapigenin and this compound called gandarusin

B. Other flavonoids are gandarusin C, D and E.

Gandarusin A is major component, steroid, volatile

oil, alkaloids and other flavonoids (gandarusin

B,C,D and E) are minor components in 70% ethanol

extract Justicia gendarussa Burm.f (Prajogo, 2007).

J.gendarussa extract have an antifertility

effect that can inhibit spermatozoa penetration in-

vitro with inhibit of hyaluronidase enzyme (Prajogo,

1998). Therefore, J.gendarussa was developed into

phytopharmaca drug. Phytopharmaca drug must be

produced based on required standar to ensure the

quality of product. The production process must

conform the standards of GMP. GMP’s requirement

including raw material, equipment, sanitation and

hygiene.

Further development of 70% ethanol

extract J.gendarussa leaves into phytopharmaca

drug, need formulation which have been conducted

by several researchers. Granules formulation from

water extract J.gendarussa leaves with avicel and

lactose as filler made by wet granulation gave poor

results because of the tablet hardness and slow

disintegration time (almost 20 minutes). Based on

that results, the filler change into lactose and corn

starch and gave good results

(Sari, 2010), the

hardness of tablets and disintegration time were

decreased. The addition of non-ionic

surfactant,tween 80 is also made to improve the

physical requirements and the dissolution rate of

gendarusin A in the granules formula (Arifani,

2012). Then developed further by replacing Tween

80 with Poloxamer 188 as surfactant. In this study,

the surfactant used is sodium lauryl sulfate.

Replacement poloxamer 188 (non-ionic) with

sodium lauryl sulphate which are anionic surfactants

is based on research conducted by Alkhamis et al.

(2003) who found that non-ionic surfactant

demonstrated the ability solubilization smaller than

the anionic and cationic surfactants on solubilization

glikazid. Additionally, poloxamer 188 has a

relatively expensive price so that less effective if

will be developed later. This formula then regarded

as the chosen formula by considering the parameters

that can produce good product as an infertility drug.

Table 1 : Relationship between % compressibility and flowability

% Compressibility

Flowability

5-12

Perfect

12-16

Good

18-21

Moderate

23-28

Poor

28-35

Poor

35-38

Very poor

> 40

Very-very poor (cohesive)

2 MATERIALS AND METHOD

2.1 Materials

Lactose (Lactose Monohydrate, Leprino USA), Corn

starch (Amylum Maydis, Cargill Bio-Chemical

China, Cab-o sil (Pluronic F-68, Sigma Life Scine

USA), Sodium Lauryl Sulfate (SLS), Methanol p.a

(Merck), Ethanol 70% Nylon membrane 0,2 µm

(Whatman), Filter holder (Millipore), Aquadest.

2.2 Methods

2.2.1 Standarized Simplicia of J.gendarussa

Nine months of J.gendarussa leaves have been

harvested. Fresh leaves then made into simplicia by

sortation (remove mechanical parts except leaf that

are not needed like bark, stem, etc) and then washed

and dried in drying cabinet at tempertaure below

50C. Dried simplicia then milled to a powder with

a certain size (Departemen Kesehatan RI, 1995).

184

2.2.2 Extraction

Gandarussa leaves powder extracted with

maseration using ethanol 70% (1:10) for 24 hours.

Re-extraction until three times. After extraction, the

solvents were allowed to evaporate using rotary

evaporator. Thus the highly concentrated ethanol

extract were obtained. The extract then stored in

refrigerator at 4

C for further use for formulation

process.

2.2.3 Formulation

Optimization were held with 3 formulas.

J.gendarussa leaves granules were prepared by wet

granulation method. Corn starch, lactose were used

as filler, sodium lauryl sulfate 1% was used as

surfactant and cab o sil was used as glidant. The

difference for each formula was on the ratio between

lactose and corn starch. Formula 2 used ratio 1:1 for

lactose and corn starch, Formula 1 used ratio 3:7 for

lactose and corn starch, Formula 3 used ratio 7:3 for

corn starch and lactose. Physical evaluation is held

to evaluate and choose the best granule.

2.2.4 Evaluation of Granules

2.2.4.1 Flow Rate and Angle of Repose

The angle of repose was determined by allowing

granules to flow through a funnel and fall freely

onto a graph paper on a horizontal surface. The time

taken for the weighed granules to flow out

completely was recorded (Bhagawan, 2015). This

was performed in triplicate.

Flow rate was obtained by the equation below:

Flow rate = weight of granules / time

The height and diameter of the resulting cone were

measured and the angle of repose is calculated from

this equation:

tan Ø =h/r

Where :

h is the height of the powder cone and r is the radius

of the powder cone

2.2.4.2 Bulk Density

The bulk density (ρ

) of granules was determined by

filling the material into a tarred graduated cylinder

to the 100 ml mark. The graduated cylinder was

weighted and the bulk density calculated as the ratio

of the sample weight to sample volume.

ρbulk= W / V

Where :

ρbulk = Apparent bulk density,

W = Weight of the sample,

V = Apparent volume of powder

2.2.4.3 Tapped Density

A suitable amount of granules was placed in a 100

ml measuring cylinder. After absorbing its initial

volume, the sample was tapped 500 times initially

followed by an additional taps of 750 times until the

difference between succeeding measurement is less

than 2% and then tapped volume, was measured, to

the nearest graduated unit. Tapped density was

calculated using

equation

ρtab = W / Vf

Where :

ρtab = Tapped Density,

W = Weight of the sample,

Vf = Tapped volume of powder

2.2.5 Moisture Content

Moisture content determination using Ohauss

electronic Moisture balance 45 with place about

0,5-1g sample in sample pan. The sample pan must

lie flat in the pan handler. Then, press the start

button to start analyze. After ten minutes, %

moisture content can read.

2.2.6 Fines Content

The determination of fines is done by inserting 100

grams of granules into a sieve with a hole diameter

of 140 mesh (the equivalent of 100 micrometers).

Then sieve vibrated for 20 minutes at a speed of 10

rpm. Weigh the amount of powder that escaped

sieve (Wade and Weller, 1994). The amount of fines

should not more than 20%. Particles that are larger

than 250 μm is relatively free flowing, whereas

particles have a size below 100 μm (fines) cause

problems in the flow properties due to the

occurrence of a large cohesive force (Aulton, 2002).

2.2.7 Statistical Analysis

Data analysis was performed on the physical

parameters of the granules and then performed

statistical analysis by one-way ANOVA (One-Way

ANOVA). To determine whether there were

significant differences between the formula, then

Composition Ratio of Lactose and Corn Starch in Granule Capsule Formulation of 70

185

followed by the Tukey-HSD test to determine any

formula that provides a meaningful difference.

Statistical analysis includes flow rate, angle of

repose, moisture content and% compressibility with

95% confidence level (α = 0.05). When Asymp. Sig.

α < (0.05), then Ho is rejected and Ha accepted.

3 RESULTS AND DISCUSSION

J.gendarussa leaves extract have a viscous

consistency therefore need filler composition like

corn starch and lactose that can improve the physical

properties of granules. With a viscous consistency

and large water content, granulation process carried

out by wet granulation to improve the flowability

and compactibilty of granule mass.

Materials used as filler are lactose and corn

starch. Lactose in the tablet formulation excipients

serves as good as it can condense the mass of

granules in the wet granulation or direct

compression and can improve the flow properties

because the lactose has a large specific gravity

(Kusumahyuning & Soebagyo, 2005). It is also the

most widely used filler because it does not react

with almost all of the ingredients. Generally,

formulation with lactose showed a good rate of drug

release, quick dry granules, disintegration time is not

very sensitive to changes in the tablet hardness

(Lachman, 1994). However, lactose may increase

the hardness of the tablet therefore need a

disintegrant to overcome. Corn starch has a lower

specific gravity than the lactose that can help the

bonds between the extract particles is not too strong

so the combination of this two excipients lactose and

corn starch can improve the physical quality of

granules extract (J. gendarussa) as phytopharmaca

drug.

The solubility of J.gendarussa extract that

partially soluble caused a slow release of the active

ingredients therefore the absorbtion and effect will

be slow. Materials with low water solubility caused

bad wetting because of their interfacial tension

between the water phase, vapor phase and solid

phase. As a result, drug will be difficult dissolved

(Lachman, 1994). This requires the addition of a

surfactant to improve the solubility.

In this study, the surfactant used was

sodium lauryl sulphate (SLS). With the addition of

this SLS, can reduce the surface tension between the

particles, which occurs damping effect that makes

the contact between the granules with media is large

so the active substance is easier to get out of the

granule and dissolve into the media. SLS as a

wetting agent can also improve the dissolution rate

of the drug due to its mechanism (Aulton, 2002).

The result of granules can be seen in fig.2,

and evaluation of each formulas can be seen in table

Figure 2: Granules formula 1,2,3 resulted from optimization

Table 2 : Physical Evaluation of Granules

Evaluation

Formula 1

Formula 2

Formula 3

Requirement

Flowability (g/s)

*3.28±1.08

6.04±1,80

6.48±1,32

4-10g/s (Good flowability)

Angle of repose (

)

*30.54±1.14

29.98±0,34

26.98±0,00

20-30

(Good flowability)

fines (%)

24.15

25.97

21.09

< 20%

Compressibility (%)

12.00

10.00

11.99

5-12% (Perfect flowability)

Moisture content (%)

1.82±0,02

2.08 ± 0,04

2.75 ± 0,02

2-4%

Yield (%)

61.63%

71.08%

78.40%

186

From the results in table 2.2, the flow rate

of the granules, formula 1 was 3.28 ± 1.08 g / s,

formula 2 was 6.04 ± 1.80 g / s, formula 3 was 6.48

± 1.32 g / s. Based on the statistic results using

ANOVA, there was no significant difference in flow

rate between formula 1,2 and 3. formula granule

flow velocity is considered good if it is in the range

of 4-10 g/s. Formula 2 and 3 meet these

requirements, while the formula 2 has a flow rate of

<4 g/s so it can be considered to have difficult flow

properties (Aulton, 2002).

The flowability can also be viewed from the

angle of repose. Angle of repose resulting from

formula 1 was 30.54 ± 1.14

, formula 2 was 29.98 ±

0.34

and formula 3 was 26.98 ± 0,00

. From the

results of statistical tests on granules extract (J.

gendarussa) , there was a significant difference

between the angle of repose formula 1 and 3,

Formula 2 and 3 on the confidence level of 0.95% (α

= 0.05). Angle of repose illustrate the magnitude of

the frictional forces between the particles, so can

demonstrate the flow properties of a granular

indirectly (Carstensen, 1977). Based on the angle of

repose, all of granules formula were meets the

criteria of the granules with good flow properties,

which have the angle of repose between 20-30

(Wells & Aulton, 1988). Good flow properties will

make the die filling fulfilled evenly so the weight of

the capsule is not distorted (Lachman et al., 1994).

Granule flow properties also have a

relationship with compressibility. Granules have a

perfect flow properties (granule flow freely) if it has

a range of 5-12% compressibility (Sucker 1982). In

formula 1,2 and 3 the compressibility respectively

were 12.07%, 9.68% and 13.11%. All formula meets

the compressibility range with perfect flow

properties. Formula 3 had the highest %

compressibility. It can be related to the high

moisture content 2.75%. Moisture content can affect

the compressibility index and flowability because

the moist powder mass will result in less free

flowing powder.

High moisture content of the F3 can also be

caused by the amount of corn starch higher than

other formulas. Corn starch is hygroscopic so the

granules will be more humid. The results of each

formula met the requirements as good granules, the

moisture content of the granules were in the range of

2% - 4%. These results can guarantee the granules

are stable during storage. Humidity of a granule will

affect the stability of the granules. The higher the

humidity, the higher the potential for microbes to

live so stability become shorter. When the moisture

content too much can lead to sticky and hard

flowing granules, but small water content will

produce a dry granule and easy fragile.

Fines content (particle size <100µm) from

all formulas were more than 20%. From all that

formula, the best formula chosen was determined

based on the evaluation has been done. Formula 2

was chosen formula because the formula 3 had a

high moisture content, it is feared the stability of the

granules is getting shorter. While the formula 1 and

2 based on the results of the statistical analysis,

flowability and angle of repose did not provide a

significant difference but in terms of the yield

obtained, compressibility and flowability, formula 2

was better than formula 1. Thus formula 2 with ratio

1:1 for lactose and corn starch was a best formula

and chosen to do the next process.

4 CONCLUSION

Granules with filler ratio 1:1 for lactose and corn

starch can result in good physical properties of

granules.

REFERENCES

Ansel, H. C., Popovich, N. G., and Allen, L. V. 1995.

Pharmaceutical Dosage Form and Drug Delivery

System, 6

ed., Malvern: Williams and Wilkins, p. 60-

65.

Arifani, G. 2012. Pengaruh Tween 80 Terhadap Laju

Disolusi Gendarusin A dalam Granul Ekstrak Etanol

70% Daun Justicia gendarussa burm. f. Untuk Sediaan

Kapsul. Skripsi. Fakultas Farmasi Universitas

Airlangga.

Aulton, M. E. 2002. Pharmaceutics : The Science of

Dosage Forms Design. London : Churchill Livingstone

Banker, G. S. and Anderson, N. R. 1989. Tablet, In:

Lachman, L., Lieberman, H. A. And Kanig, J. L.

(Eds). Teori dan Praktek Farmasi Industri, edisi ketiga,

Vol II, Jakarta: Universitas Indonesia.

Bhagawan, W.S. 2015. Formulasi dan Uji Disolusi Granul

Ekstrak Etanol 70% Terfraksinasi Daun Gendaarusa.

Thesis. Fakultas Farmasi Universitas Airlangga.

Carstensen. 1977. Pharmaceutics of Solid and Solid

Dosage Forms. New York: John Willey and Sons.

Carstensen, J.T. and Rhodes, C.T., 2000, Drug Stability

Principles and Practices, Third Edition, Revised and

Expanded, Marcel Dekker, Inc., New York : 238 –

381.

Chakravarty, A. K., Dastiar, P. P. G., and Pakrashi, S. C.

1982. Simple aromatic amines from Justicia

gendarussa 13C NMR Spectra of the bases and their

analogues. Tetrahedron. Elsivier, 18 (12):1797-1802.

Composition Ratio of Lactose and Corn Starch in Granule Capsule Formulation of 70

187

Dalimartha, S. 2001. Atlas Tumbuhan Obat Indonesia,

Jilid 1, Jakarta: Trubus Ariwidya.

Departement of Health. 2002. British Pharmacopoeia.

London: The Stationary Office. p. 1003, A 241-242.

Departemen Kesehatan RI. 1995. Farmakope Indonesia.

Edisi IV. Jakarta : Dirjen POM.

Departemen Kesehatan RI. 1995. Materia Medika

Indonesia. Jilid VI. Jakarta: Departemen Kesehatan RI.

Departemen Kesehatan RI. 2000. Parameter Standar

Umum Ekstrak Tumbuhan Obat. Jakarta: Departemen

Kesehatan RI.

Dhirendra, K., Lewis, S., Udupa, N., and Atin, K. 2009.

Solid Dispersion, India, Manipal College of

Pharmaceutical Science. p. 234-246.

EMEA., 1999. Working Part on Herbal Medicinal

Products (HMPWP), Stability testing of HD (Herbal

Drug), HDP (Herbal Drug Preparation), and HMP

(Herbal Medicinal Product), Guidelines 25 : 48.

Feher, M., and Schmidt, J. M. 2003, Property

Distributions: Differences Between Drugs, Natural

Products, And Molecules From Combinatorial

Chemistry, J. Chem. Inf. Comput. Sci. 43, 1, 218-227

Gordon, R. E., Rosanske, T. W., Fonner, D. E., Anderson,

N. R., and Banker, G. S. 1990. Granulation

Technology and Tablet Characterization. In: Lachman,

L., Lieberman, H. A., Schwartz, J. B. (Eds),

Pharmaceutical Dosage Forms: Tablets, 2

ed, Vol. 2,

New York: Marcel Dekker, Inc.

Gunsel, W. C. and Kanig, J. L. 1976. Tablet, In: Lachman,

Lieberma, H. A. and Kanig J. L., The Teory and

Practice of Industrial Pharmacy, 2

Ed., Lea and

Febiger, Philadelphia.

Gupta, R. S., and Sharma, R. 2006. A Review on

Medicinal Plants Exhibiting Antifertility Activity in

Males. Natural Product Radiance. Vol. 5 (5), p. 389-

410.

Handa, S. S., Khanuja, S. P. S., Longo, G., and Rakesh, D.

D. 2008. Extraction Technologies for Medicinal and

Aromatic Plants. Itali: International centre for science

and high technology. pp.21-25.

Harborne, J. B., 1987. Metode Fitokimia Penuntun Cara

Modern Menganalisis Tumbuhan, Edisi kedua.

Bandung: Institut Teknologi Bandung Press.

Heyne. 1987. Tumbuhan Berguna Indonesia. Jilid III.

Terjemahan Badan Litbang Kehutanan. Jakarta:

Yayasan Sarana Wana. hal 1759.

Kiren, Y., Deguchi, J., Hirasawa, Y., Morita, H., and

Prajogo, B. 2014. Justidrusamides A-D, new 2-

aminobenzyl Alcohol Derivatives from Justicia

gendarussa. Journal of Natural Medicines. Vol. 68, pp.

754-758.

Kusumahyuning, R. & Soebagyo., Sulihtyowati, S. 2005.

Pengaruh Laktosa dan Povidon dalam Formula

Ekstrak Kaempferia galanga L. Secara Granulasi

Basah. Majalah Ilmu Kefarmasian. Vol. II, No. 16,

110-115.

Lachman, L., Lieberman H.A., Kanig J.L. 1994. Teori dan

Praktek Farmasi Industri edisi III. Jakarta : UI Press.

Lieberman, H.A., Lachman, L., Schwartz, J.B. 1990.

Pharmaceutical Dosage Forms. New York : Marcel

Dekker.

Ncube, N. S., Afolayan, A. J., and Okoh, A. I. 2008.

Assessment Techniques of Antimicrobial Properties of

Natural Compounds of Plant Origin: current methods

and future trends. African Journal of Biotechnology.

Vol 7, pp.1797-1806.

Prajogo, B. E. W., A. Khoiril, IGP Santa dan Soeharno.

1997. Efek Ekstrak Diklormetan dan Ekstrak Metanol

Daun Gendarussa vulgaris Ness pada

Spermatogenesis tikus, Simposium PERHIPBA IX,

Universitas Gadjah Mada, Yogyakarta.

Prajogo, B. E. W., NS. Matty, IGP. Santa and PS. Onny.

1998. Efek Ekstrak Diklormetan dan Ekstrak Metanol

Daun Gendarussa vulgaris Ness pada Aktivitas Enzim

Spermatozoa Kelinci. Symphosium POKJANAS TOI 8

VIII Universitas Brawijaya, Malang.

Prajogo, B. E. W. 2002. Aktivitas Antifertilitas Flavonoid

Daun Gendarusa Vulgaris Ness. Penelitian

Eksperimental Pencegahan Penetrasi Spermatozoa

Mencit dalam Proses Fertilisasi In Vitro. Disertasi.

Program Pasca Sarjana Universitas Airlangga

Surabaya.

Prajogo, B. E. W., Dudi, S., dan Mulya, H. S. 2007.

Analisis Gendarusin A pada tanaman Budidaya

Justicia gendarussa Burm f. Jurnal Farmasi Indonesia.

3: 176-180.

Prajogo, B. E. W., Pramesti, D., Musta’ina, S., Winarso,

H., Radjaram, A., Suharjono., Zaini, N. C., Flourisa,

J., Anggraeni, M. 2011. Clinical Trial: The Use of

Justicia gendarussa Burm. f. as Male Contraception.

APCRSHR 6. Yogyakarta: Indonesia.

Prajogo, B. E. W. 2014. Autentik Tanaman Justicia

gendarussa Burm. f. Sebagai Bahan Baku Obat

Kontrasepsi Pria. Surabaya: Airlangga University

Press dengan LP3 UNAIR.

Pratama, B. O. 2012. Penentuan Standar Umum Ekstrak

Etanol 70% Daun Justicia gendarussa Burm. f.

Skripsi. Fakultas Farmasi Universitas Airlangga.

Radji, M., Oktavia, H., Suryadi, H. 2008. Pemeriksaan

Bakteriologis Air Minum Isi Ulang Di Beberapa Depo

Air Minum Isi Ulang di Daerah Lenteng Agung dan

Srengseng Sawah Jakarta Selatan. Majalah Ilmu

Kefarmasian, Vol 5(2) : 101-109

Rajakumar, N., and Shivana, M. B. 2009. Ethno-medical

Application of Plants in the Eastern Region of

Shimoga Distric. Journal Ethnopharmacology. Vol

126, pp.64-73.

Rizqa, O, D., 2010. Standardisasi Simplisia Daun Justicia

gendarusssa Burm f. Dari Berbagai Tempat Tumbuh

(Daerah Mojokerto lahan 1, Mojokerto Lahan II, dan

Ponorogo). Skripsi, Fakultas Farmasi Universitas

Airlangga, Surabaya.

Rowe, R. C., Paul, J. S., Sian, C. O. 2009. The Handbook

of Pharmaceutical Excipients. 6

Ed, London:

Pharmaceutical Press and American Pharmacist

Association.

Sari, M.A. 2010. Pengembangan Formula Granul Ekstrak

Etanol 70% Daun Justicia gendarussa Burm.f.

188

Sebagai Sediaan Fitofarmaka. Skripsi, Fakultas

Farmasi Universitas Airlangga, Surabaya.

Staniforth, J. N. 1988. Powder Flow. In: Aulton, M.,

Pharmaceutica: The Science Dosage Form Design,

New York: Churchill Livingstche.

Sucker, H. 1982. Test Methods for Granulates, In Pharm

Ind, 44

Ed, number 3, Switzerland.

United State Pharmacopoeia Convention. 2003. The

United State Pharmacopeia 26-National Formulary.

United States Pharmacopeia Convention. 2002. The

United State Pharmacopeia 25-National Formulary.

Wells, J. L. and Aulton, M. E. 1988. Preformulation, in

Aulton, M. E., Editor, Pharmaceuticals The Sciences

Dosage Form Design. London: Churcill Livingstone.

WHO. 1999. WHO Monograph on Selected Medicinal

Plants. Vol.I, Geneva: WHO.

Zheng, Jack. 2009. Formulation and Analytical

Development for Low Dose Oral Drug Products. New

Jersey: John Wiley & Sons, Inc.

Composition Ratio of Lactose and Corn Starch in Granule Capsule Formulation of 70

189