Formulation Study for Orally Disintegrating Tablet Using

August 2011 959Regular Article

Orally disintegrating tablets are widely accepted in currentmedical practice as patient-friendly alternatives to conven-tional oral solid dosage forms, such as regular tablets andcapsules, especially by those who have problems or difficul-ties swallowing (e.g. elderly and pediatric patients, and pa-tients with cerebrovascular event) and those requiring fluidrestriction. Zydis technology, developed by Cardinal Healthin the early 1980s, is said to be the origin of the orally disin-tegrating tablet technology. There are currently 3 classes oforally disintegrating tablet technology, namely, crystalliza-tion control,1—4) process control5—7) and formulation de-sign.8,9) Characteristically, technologies for both types ofcrystallization control and process control improve the disin-tegrating speed of the tablets. However, the resulting tabletstend to be too soft, and special additives included in the for-mulations, or special production machinery and complexprocedures are required for their production. Therefore, highmanufacturing costs and low productivity are problems asso-ciated with these 2 classes of technologies. On the otherhand, tablets that are based on the formulation design showreasonable hardness, albeit with slightly lower disintegrabil-ity compared with those of the other 2 technologies. Further,the formulation design technology enables production oforally disintegrating tablets with conventional tableting ma-chinery, and thus contributes to cost effectiveness and stableproduction. Recently, formulations containing crospovi-done10) or corn starch11) as a disintegrant, a saccharide or adisaccaride as a filler,12) sodium stearyl fumarate13) or a su-crose ester of a fatty acid14) as a lubricant were reported. Inaddition, formulation optimization using design of experi-ments (DOE)15—17) and improvements in manufacturingprocesses18) has been demonstrated. Accordingly, the qualityof orally disintegrating tablets is continuously improving.

In this study, we focused on formulation design technol-ogy, and evaluated various types of binders used in the wetgranulation process. D-Mannitol (Man) and corn starch (CS)

were respectively used as a filler and a disintegrant of orallydisintegrating tablets. We also employed DOE to analyze andidentify formulations containing a suitable binder. Becausethe study aimed to construct a model applicable to the for-mulation of orally disintegrating tablets with consideration ofthe ethical aspects involved in testing disintegration of tabletsin humans, only placebo formulations that lacked inclusionof drugs were examined.

ExperimentalMaterials D-Mannitol (Man: Mannit P) was purchased from Mitsubishi

Shoji Foodtech Co., Ltd. (Tokyo, Japan). Corn starch (CS) was purchasedfrom Nippon Starch Chemical Co., Ltd. (Osaka, Japan). Partly pregela-tinized starch (PGS: Starch 1500) was purchased from Colorcon Japan, Llc.(Shizuoka, Japan). D-Sorbitol (Sor: Sorbogen) was obtained from SPIPharma, Inc. (Wilmington, U.S.A.). Macrogol 4000 (Mac) was obtainedfrom NOF Corp. (Tokyo, Japan). Hypromellose (Hyp: TC-5E) was pur-chased from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Hydroxypropyl-cellulose (HPC: HPC-SL) was purchased from Nippon Soda Co., Ltd.(Tokyo, Japan). Povidone (PVP: Povidone K30) was obtained from ISP Ltd.(Wayne, U.S.A.). Light Anhydrous Silicic Acid (LASA: Adosolidar 101)was purchased from Freund Co., Ltd. (Tokyo, Japan). Calcium Stearate(CaSt) was purchased from Nitto Kasei Kogyo Co., Ltd. (Kanagawa, Japan).All other chemicals were of regent grade.

Preparation of Tablets 1) Preparation of Tablets with Different Typesof Binder: Various binders were used for tablet formulations (Table 1), andthe tablets were prepared as follows. Each binder was dispersed or dissolvedin purified water to make a binding solution. Man was placed in a fluid-bedgranulator (LAB-1, Powrex Corp., Hyogo, Japan), and granules were pre-pared while spraying a binding solution mist. This was followed by sizingwith a powermill (P-02S, Dalton, Tokyo, Japan) with a screen size of1.5 mm in diameter. CS, CaSt and LASA were then added to the resultinggranules in the ratio shown in Table 1, and mixed by hand for 2 min in aplastic bag. The mixture was set in a rotary tablet press (Correct 12HUK,Kikusui Seisakusho Ltd., Kyoto, Japan) and compressed into tablets usingthe following settings: punch and die diameter of 8 mm, curvature of 12R,compression force of 4, 8 or 12 kN and tablet weight of 200 mg.

2) Preparation of Tablets Containing Granules Prepared According to aCentral Composite Design: Granule formulations containing CS, PGS andMan were prepared using a central composite design for 2 variables, CS andPGS (Table 2). A dispersion of PGS in purified water was used as a bindersolution. Man and CS were placed in the fluid-bed granulator, and the gran-

Formulation Study for Orally Disintegrating Tablet Using PartlyPregelatinized Starch Binder

Kazuki MIMURA,a,b Ken KANADA,b Shinya UCHIDA,a Masaki YAMADA,b and Noriyuki NAMIKI*,a

a Department of Pharmacy Practice and Science, School of Pharmaceutical Sciences University of Shizuoka; 52–1 Yada,Suruga-ku, Shizuoka 422–8526, Japan: and b Pharmaceutical Research & Development, Kissei Pharmaceutical Co., Ltd.;19–48 Yoshino, Matsumoto, Nagano 399–8710, Japan.Received January 28, 2011; accepted May 6, 2011; published online May 17, 2011

In this study, we aimed to design orally disintegrating tablets by employing a formulation design approachthat enables the production of such tablets in the same facilities used for the production of solid dosage forms onan industrial scale. First, we examined the relationships between the types of binders used in the tablets and theproperties of orally disintegrating tablets prepared by the wet granulation method. Results revealed that partlypregelatinized starch is a relatively suitable binder for orally disintegrating tablets as it also serves as a disinte-grant. Next, we employed a central composite design for 2 factors, namely, corn starch and partly pregelatinizedstarch, in order to design granules suited for orally disintegrating tablets composed of D-mannitol, corn starch orpartly pregelatinized starch. The effects of these 2 factors on 3 types of responses, namely, 50% granule size,compressing index and disintegrating index, were analyzed with a software package, and responses to changes inthe factors were predicted. This study investigated the effects of binder type and binder content in orally disinte-grating tablets, and provided evidence that the binder exerts a strong influence on tablet properties, and is there-fore an important component of orally disintegrating tablets.

Key words orally disintegrating tablet; binder; partly pregelatinized starch; hardness; disintegration time; central composite design

Chem. Pharm. Bull. 59(8) 959—964 (2011)

© 2011 Pharmaceutical Society of Japan∗ To whom correspondence should be addressed. e-mail: [email protected]

ules were prepared while spraying a binding solution mist. Granules werethen filtered through a No. 18 mesh sieve, and 490 g of the resulting size-controlled granules were mixed with 2.5 g of LASA and 7.5 g of CaSt with aV-type blender (DV-1, Dalton, Tokyo, Japan) for 2 min. The mixture was setin the rotary tablet press to make tablets using the following settings: punchand die diameter of 8 mm, curvature of 12R, compression force of 4, 6, 8, 10or 12 kN and tablet weight of 200 mg.

Viscosity of Binder Solution The viscosity of each binding solution(6% w/w) and slurry was measured with a rotating viscometer (VISCONICEMD, Toki Sangyo Co., Ltd., Tokyo, Japan) at 100 rpm at 20 °C.

Granule Characteristics Granules were mesh controlled and theirweight-standard distributions were obtained with a sonic sifter (L-3PS,Seishin Enterprise Co., Ltd., Tokyo, Japan). The 50% granule sizes werethen calculated using a regression equation. Bulk density was measured witha powder tester (PT-N, Hosokawa Micron Corp., Osaka, Japan).

Tablet Characteristics Hardness of tablets was measured with a hard-ness tester (TS-75N, Okada Seiko Co., Ltd., Tokyo, Japan). Five tablets weretested for each formulation, and the mean hardness was calculated. Oral dis-integration time was examined both in humans and with an orally disinte-grating tablet tester (ODT-101, Toyama Sangyo Co., Ltd.). Five healthy menwere asked to take a tablet and roll it gently with their tongue in the oral cav-ity. The time required for tablet disintegration was measured, and the meantime for the 5 individuals was obtained. The orally disintegrating tablettester was preliminarily evaluated to find the conditions that correlate with invivo results in humans. Five tablets of each formulation were tested with thetester under pre-determined conditions (beaker temperature: 37�2 °C; rotat-ing speed: 140 rpm; weight: 20 g; screen size: 2.0 mm in diameter), and themean value was obtained.

Statistical Analysis Since correlations between compression force andtablet hardness, and tablet hardness and disintegration time, were observed,the slope of the linear regression curve for each correlation was defined asfollows. 1) Compressing index (N/kN): the slope of the regression line oftablet hardness on compression force. A higher index value indicates that anincremental increase in tablet hardness, in response to an increase in com-pression force, will be harder. In other words, formulations with a highindex value indicate good compressibility. 2) Disintegrating index (s/N): theslope of the regression line of oral disintegration time on tablet hardness. Alower index value indicates that tablet disintegrability is sufficient regardlessof tablet hardness. JMP6 (SAS Institute Japan Ltd., Tokyo, Japan) softwarewas used to analyze the effects of 2 factors (CS and PGS) on 3 responses(50% granule size, compressing index and disintegrating index) by perform-ing analysis of variance (ANOVA) tests, and to predict factors and responsesinvolving second-order interactions.

Results and DiscussionThree tablet-making methods are used in formulation de-

sign technology. The first is the direct compression methodthat produces tablets by directly compressing a mixture ofraw materials. The second is the dry granulation method,which involves preparation of dry granules from raw materi-als before tablet compression. The third is the wet granula-tion method, where granules are made from raw materialswith the aid of a binder solution prior to tablet compression.Modification of materials is easier in the third method than inthe other two; therefore, flexible control of compressibilityand disintegrability, by altering the manufacturing condi-tions, is its distinctive feature. A binder is added as a solutionor slurry in the wet granulation method and helps with theformation of interparticle bonds and growth of granules. Italso enhances the hardness of the resulting tablets.

Many studies on the formulation design of orally disinte-grating tablets have been reported, and many of them investi-gated fillers, disintegrants and lubricants. With respect tobinders, compounds that do not strongly enhance interparti-cle bond strength, such as solutions of a carbohydrate or asugar alcohol19) and a slurry of CS or crospovidone,20) werepreviously tested. Low interparticle bond strength correlateswith good disintegrability of tablets, but also associates withtableting problems and deterioration in tablet hardness,which are not desirable properties for industrial-scale pro-duction. Amongst the widely used binders are cellulose andits derivatives, starch and its derivatives and synthetic poly-

960 Vol. 59, No. 8

Table 1. Formulation of Tablets Using Different Types of Binders

Formulation (mg)Function Component

A-1 A-2 A-3 A-4 A-5 A-6 A-7

Filler Man 172.48 172.48 172.48 172.48 172.48 172.48 172.48

Binder Man 3.52 — — — — — —PGS — 3.52 — — — — —Sor — — 3.52 — — — —Mac — — — 3.52 — — —Hyp — — — — 3.52 — —HPC — — — — — 3.52 —PVP — — — — — — 3.52

Disintegrant CS 20 20 20 20 20 20 20Lubricant CaSt 3 3 3 3 3 3 3Glidant LASA 1 1 1 1 1 1 1Total 200 200 200 200 200 200 200

Table 2. Formulation of Granules Using Partly Pregelatinized Starch withCentral Composite Design

Variable level Actual value

Formulationin formulation

CS PGS CS (%) PGS (%) Man (%)

B-1 �1 �1 5 1 94B-2 1 �1 19 1 80B-3 �1 1 5 5 90B-4 1 1 19 5 76B-5 ø

—2 0 22 3 75

B-6 �ø—2 0 2 3 95

B-7 0 ø—2 12 6 82

B-8 0 �ø—2 12 0 88

B-9 0 0 12 3 85B-10 0 0 12 3 85B-11 0 0 12 3 85

Center points of formulations were repeated three times to estimates the experimen-tal error (B-9, B-10 and B-11).

mers, all of which demonstrate diverse functions and charac-teristics. In the present study, we compared a wide range ofbinders of orally disintegrating tablets to identify one that en-hances interparticle bond strength to an adequate level for in-dustrial-scale production, and also produces good disintegra-bility of tablets. Binders enhance interparticle bond strength,while decreasing disintegrability of tablets in a dose-depen-dent fashion. Therefore, it is important to examine carefullythe types and concentrations of binders for designing formu-lations of orally disintegrating tablets.

Binder for Orally Disintegrating Tablet As shown inTable 1, 7 formulations were prepared using 7 types ofbinders, and tablets were prepared from each formulation bythe wet granule method. A compression force of 4, 8 or12 kN was used. The viscosity of each binder and the 50%granule size of granules are shown in Table 3. The viscosityof the binder solution containing HPC was the highest, whilethat of the binder solutions containing Man, Sor and Macwere the lowest. Size distribution of the tablet material is animportant factor influencing the tableting process. When thegranule size of the material is too small, tableting problems,attributed to poor flowability and compressibility, tend tooccur. On the other hand, excessively large-sized granulescause deterioration in filling properties and compression fail-ure. Therefore, tablet material suitable for industrial-scaleproduction needs to have an appropriate granule size.

The relationship between compression force and tablethardness is shown in Fig. 1a. Regardless of the types of for-mulation, tablet hardness increases in line with increasedcompression force. Hardness of tablets containing PVP as abinder was the most responsive to increases in compressionforce, while that of tablets containing Man was the least re-sponsive. It was also shown that tablet hardness is easily in-creased by increasing the compression force, when PGS,Hyp, HPC and PVP are used as the binder. It is consideredthat the highest hardness of tablets containing PVP resultedfrom the binding strength of PVP itself and lower viscosityof binder solution enabled uniformly-distributed granules.21)

The relationship between tablet hardness and disintegrationtime is shown in Fig. 1b. For a given tablet hardness, tabletscontaining Hyp are the most difficult and slowest to disinte-grate, while those containing Man are the easiest and fastestto disintegrated. Because the hardness of tablets containingMan was insufficient, we performed a separate experiment inan attempt to improve that hardness. However, we encoun-tered tableting problems, and could not produce Man-con-taining tablets with sufficient hardness. We estimate that thecriteria for suitable characteristics of orally disintegratingtablet are both �50 N for hardness and �40 s for disintegra-

tion time. Among the binders tested, Sor, HPC and PVP aswell as PGS showed acceptable characteristics. In addition,PGS appeared to be the better profile than others since it con-sistently and independently adds good disintegrability totablets to increase tablet hardness. It is generally believedthat the disintegrating time of immediate-release tablets andorally disintegrating tablets increases as their hardness in-creases. Our results have demonstrated that an increase intablet hardness has a different extent of impacts on disinte-grating time depending on the type of binder used. Taken to-gether, it was shown that PGS can be a suitable binder for theproduction of orally disintegrating tablets because it pro-duces granules with appropriate size and contributes to goodcompressibility and tablet disintegrability. A scanning elec-tron microscope image of a granule containing PGS is shownin Fig. 2. As assumed, CS and Man were observed as rod-likeand spherical particles, respectively, and PGS was observedas irregular particles connecting Man and CS. In addition toits role as a binder, PGS is known to enhance tablet disinte-grability by its ability to induce swelling.22) It has been sug-gested that PGS-containing tablets make suitable orally dis-integrated tablets, because both PGS and CS contribute togood disintegrability.

Central Composite Design for Granules of Orally Dis-integrating Tablet Granules containing CS, PGS and Manwere prepared according to the formulations shown in Table2. A second-order model of the rotatable central compositedesign with 2 factors, namely CS and PGS, wherein the cen-ter points run 3 times, was used. Five levels of compressionforce, 4, 6, 8, 10 and 12 kN, were tested for tableting. As

August 2011 961

Table 3. Viscosity of Binder Solution and 50% Granule Size

FormulationViscosity 50% Granule size (mPa · s) (mm)

A-1 2.4 72A-2 7.0 116A-3 2.6 90A-4 2.8 87A-5 16.8 190A-6 36.5 173A-7 5.5 132

Fig. 1. Relation between Compression Force and Hardness (a), and be-tween Hardness and Disintegration Time with ODT-101 (b)

Results are expressed as mean�S.D. (n�5). A-1 (�, Man), A-2 (�, PGS), A-3 (�,Sor), A-4 (�, Mac), A-5 (�, Hyp), A-6 (�, HPC), A-7 (�, PVP).

Fig. 2. Scanning Electron Micrograph of a Granule Using Partly Pregela-tinized Starch as a Binder

shown in Table 2, although Man, as well as PGS and CS, canbe considered as variables, Man was used as a filler and itscontent did not vary largely depending on the type of formu-lation. Therefore, we did not include this component in thefactors of the central composite on the assumption that it hasonly minor influences on compressibility and disintegrability.

The relationship between compression force and tablethardness is shown in Fig. 3a, and the relationship betweentablet hardness and disintegration time is shown in Fig. 3b.The dependence of the increase in tablet hardness on the in-creases in compression force varied across the formulations.Increases in compression force made marked improvementsin the hardness of tablets made from some formulations,while small improvements in the hardness of tablets weremade from the others. Nevertheless, hardness of all formula-tions increased linearly with increasing compression force,albeit at different rates. With respect to disintegration time,increases in tablet hardness correlated with longer tablet dis-integration time, regardless of formulation type. The extentof the influence of an increase in hardness on disintegrationtime varied across the formulations. Some formulationsshowed little increases in disintegration time in line with in-creases in hardness, while others showed marked increases.As shown in Fig. 1b, tablets containing binders such as Hypshowed a sudden large increase in disintegration time whentablet hardness reached a certain level. When PGS was usedas a binder, the disintegration time of the tablets increasedlinearly with increases in hardness, independent of the PGSconcentration in the formulation. On the basis of the above

findings, we defined the slope of the regression line of tablethardness on compression force and that of tablet disintegra-tion time on tablet hardness as the compressing index and thedisintegrating index, respectively. We used these findings asindexes for designing orally disintegrating tablets. A highcompressing index and a low disintegrating index are charac-teristics of formulations suitable for orally disintegratingtablets. The 50% granule size, compressing index and disin-tegrating index of each tested formulation are shown in Table4. The 50% granule size varied widely from 46 to 217 mm.The compressing index ranged from 2.28 to 8.58, while thedisintegrating index ranged from �0.01 to 1.13.

Formulation Analysis Using Design of ExperimentsThe effects of the factors (CS and PGS) on the 50% granulesize, compressing index, and disintegrating index, were ana-lyzed using JMP6 statistical analysis software, and the resultsof ANOVA and sorted effect estimates are shown in Table 5,Table 6 and Table 7, respectively. The p values for the aboveresponses were 0.0017, 0.0038 and 0.0019, respectively, indi-cating that 3 responses change depending on the amounts ofCS and PGS. The sorted effect estimates showed that the in-tercept and PGS had the strongest impacts, and second-orderCS had effects on the 50% granule size. The intercept andPGS influenced the compressing index, while CS, PGS andsecond-order CS impacted on the disintegrating index. The pvalues for these factors were less than 0.05, indicating thatthe effects of these factors on corresponding responses were

962 Vol. 59, No. 8

Fig. 3. Relation between Compression Force and Hardness (a), and be-tween Hardness and Disintegration Time in Oral Cavity (b)

Results are expressed as mean�S.D. (n�5). B-1 (�), B-2 (�), B-3 (�), B-4 (�), B-5 (�), B-6 (�), B-7 (�), B-8 (∗), B-9 (—), B-10 (—), B-11 (—).

Table 4. 50% Granule Size, Compressing Index and Disintegrating Indexof Formulations Using Partly Pregelatinized Starch with Central CompositeDesign

50% Compressing Disintegrating Formulation Granule size index index

(mm) (N/kN) (s/N)

B-1 89 5.23 0.19B-2 76 4.62 0.01B-3 203 7.55 1.01B-4 175 7.51 0.32B-5 140 5.99 0.16B-6 143 6.95 1.13B-7 217 8.58 0.53B-8 46 2.28 �0.01B-9 123 6.60 0.17B-10 122 6.19 0.13B-11 106 6.60 0.20

Table 5. ANOVA and Sorted Effect Estimates for 50% Granule Size

Analysis of varianceSource DF Sum of squares Mean square F ratioModel 5 27141.948 5428.39 70.8738Error 5 382.961 76.59 Prob�FC. total 10 27524.909 0.0017*

Sorted effect estimatesTerm Estimate S.E. t ratio Prob�| t |Intercept 117.01397 5.045095 23.19 �0.001*CS (%) �5.603535 3.078527 �1.82 0.1284PGS (%) 55.235294 3.001809 18.4 �0.001*CS (%)�PGS (%) �3.75 4.375851 �0.86 0.4306CS (%)�CS (%) 12.074886 3.657529 3.30 0.0214*PGS (%)�PGS (%) 6.5013623 3.363939 1.93 0.1111

∗ p�0.05.

significant. Contour plots depicting the relationships of CSand PGS with 3 responses are shown in Fig. 4. While Tables5, 6 and 7 present the mathematically obtained predicted response values, the contour plots provide visual and simpleinformation on factor-dependent changes in responses. Con-tour lines run vertically in the 50% granule size and com-pressing index plots, indicating that these responses tend tobe influenced by PGS. On the other hand, contour lines rundiagonally in the disintegrating index plot, indicating thatthis response is under the influence of PGS and CS.

In this study, we established the effectiveness of PGS as abinder of orally disintegrating tablets. Furthermore, we em-ployed DOE and formulation analysis to examine propertiesof tablets in connection with their formulation, and success-fully obtained effective information for designing orally dis-integrating tablets. On the basis of the findings of this study,we intend to perform further studies to optimize the formula-tion containing active ingredients, and furthermore, the tabletproduction procedure.

August 2011 963

Fig. 4. Contour Plots for 50% Granule Size (a), Compressing Index (b) and Disintegrating Index (c)

Table 6. ANOVA and Sorted Effect Estimates for Compressing Index


Sorted effect estimatesTerm Estimate S.E. t ratio Prob�| t |Intercept 6.4735639 0.328415 19.71 �0.001*CS (%) �0.250126 0.200399 �1.25 0.2672PGS (%) 1.7247059 0.195405 8.83 0.0003*CS (%)�PGS (%) 0.1425 0.28485 0.50 0.6381CS (%)�CS (%) 0.0544584 0.23809 0.23 0.8281PGS (%)�PGS (%) �0.417566 0.218979 �1.91 0.1148

∗ p�0.05.

Table 7. ANOVA and Sorted Effect Estimates for Disintegrating Index


Sorted effect estimatesTerm Estimate S.E. t ratio Prob�| t |Intercept 0.1638771 0.064424 2.54 0.0517CS (%) �0.279116 0.039312 �7.10 0.0009*PGS (%) 0.2282353 0.038332 5.95 0.0019*CS (%)�PGS (%) �0.1275 0.055878 �2.28 0.0714CS (%)�CS (%) 0.2204247 0.046705 4.72 0.0052*PGS (%)�PGS (%) 0.030113 0.042956 0.70 0.5146

∗ p�0.05.

ConclusionThe purpose of this study was to provide basic research

findings to aid the design and formulation of orally disinte-grating tablets, without providing information on the optimalformulation of the final tablet medicine. By focusing on theformulation design technology suited for industrial-scale pro-duction and employing the wet granulation method, we testedseveral candidates and suggested PGS as a relatively suitablebinder for orally disintegrating tablets. We further analyzedthe relationship between the different PGS-containing formu-lations and the properties of the resulting tablets using DOE,and revealed the levels of influence of each formulation ontablet properties. Although very few studies have investi-gated binders for orally disintegrating tablets to date, ourstudy demonstrated that binders have strong impacts ontablet properties. Taken together, we provided evidence thatselecting an appropriate binder and its content is extremelyimportant in designing orally disintegrating tablets.

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Formulation Study for Orally Disintegrating Tablet Using