PREPARATION AND EVALUATION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/33464/9/09...1 (102) Modified Starch Worldwide, starch is one of the most widely used excipients in

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CHAPTER 5

PREPARATION AND EVALUATION

OF

RAPIDLY DISINTEGRATING TABLETS

CONTAINING BLENDS

OF

PHYSICALLY MODIFIED STARCH

AND

MICROCRYSTALLINE CELLULOSE/ LACTOSE

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Modified Starch

-—Vl*

CHAPTER 5

Preparation and Evaluation of Rapidly Disintegrating

Tablets Containing Blends of Physically Modified Starch_ and Microcrvstalline Cellulose/ Lactose

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i

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Section Content- “jm’ ••ww fr - *•

I

5.1 Introduction»

5.2 Materials

5.3 Methodsl

5.3.1 Physical Modification of Starch

5.3.2 Water Solubility

Tableting of Physically Modified Starch

Preparation of Tablets of Modified Starch and

MCC_

Preparation of Tablets of Modified Starch and

Lactose

nLinCSOCZ

5.3.3

5.3.4

5.3.5»

Results and Discussion5.4r

PhysicallyModified Starch

Factorial Design

5.4.3 |Blend of Physically Modified Starch and MCC

5.4.1i

t

5.4.2*

T:

i

4

5.4.4 sica—%

Conclusions5.5*

References5.5<

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4

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Modified Starch

List of Tables

Table 5.1 Design Layout and Results of Measured Responses.

Table 5.2 Results of Regression Analysis

Table 5.3 Data Matrix and Steps for Generating Intermediate Values

Table 5.4 j Computed Values of Crushing Strength - Reduced Model

Table 5.5 Data Matrix for Sum of Squares of Residuals

Table 5.6 Matrix for Absolute Percentage Difference

=

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%

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Modified Starch

List of Figures

Figure 5.1 Histogram of Native and Modified Starch

Figure 5.2 Response Surface Plot for Crushing Strength

(Starch+MCC)

Figure 5.3 Contour Plot for Crushing Strength (Starch+MCC)

Figure 5.4 Effect Plot for Crushing Strength (Starch+MCC)

Figure 5.5 Response Surface Plot for Disintegration Time

(Starch+MCC)

Figure 5.6 JContour Plot for Disintegration Time (Starch+MCC)

Figure 5.7 I Effect Plot for Disintegration Time (Starch+MCC)7 ---1 ’r , " f - -ÿ y ~ H wmm — . .p !ÿÿÿÿ_, ,, — — , — --*y ,ÿÿÿ * — - y . p I 1 —— 1 IT T»‘. IL1-"."- - 1 ~ -

Figure 5.8 TCombined Contour Plot for Modified Starch

Figure 5.9 TResponse Surface Plot for % Friability (Starch+Lactose)

Figure 5.10 Contour Plot for % Friability (Starch+Lactose)

Figure 5.11 ! EffbcfpTotlbr % Friability (Starch+Lactose)

0

0

%

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Modified

5.1. INTRODUCTION

Sam and Fokkens [1] reported tablet as the most popular dosage form.

Excipients are added in tablet formulations for various reasons.

Excipients are defined as any component other than the active

substance(s) intentionally added to develop a dosage form. They have

long been considered “inert” components of a dosage form. However,

they may have toxicological (mercurial), pharmacological (sugar

alcohol), immunological (lactose, tartrazine) and psychological (placebo)

implications.

During drug product development, excipients are chosen to perform a

variety of functions in the drug product. These functions are divided into

three basic categories: stability of the drug substance, alteration in

absorption, and manufacturability on a production scale. The functions

related to the manufacturability are further divided into two categories:

excipients that are necessary to make a particular dosage form (so called

dosage form necessities such as diluent, disintegrant, etc.) and excipients

that are required to perform specific technological functions in the dosage

, gelling agent, emulsifying agent and ointment bases

needed to make gels, emulsions and ointments respectively. For the

ment of solid dosage forms, important technological functions are

form. For example

are

develop

compaction, lubrication and flow [2]. Besides the three basic categories,

there are other important points such as patient compliance, cost, etc.

The most important requirements for tableting are good flowability and

compatibility. Wet granulation and use of suitable binder/s are known

93

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Modified Starch

approaches to improve flow and compressibility of granules leading to

weight uniformity of tablets and formation of robust tablets. It has been

reported that the type and concentration of binders are the major

determinants in controlling the quality of granules [3].

The compaction of a granulation depends on granule porosity, which is

controlled by the quantity of binder solution, granulation time and

blending time with the lubricant [2]. Hence, these factors were kept at a

constant level in the present investigations.

Opata et al. [4] reported that during wet granulation, the amount of water

(100 ml) necessary to granulate lactose was less important in controlling

the quality of tablets than the amount of water (170 ml) required to

granulate a formulation containing cellulose.

Chalmers and Elworthy [5] explored the effect of wet mixing time on

oxytetracycline granules and tablet properties. An increase in wet mixing

time resulted in a decrease in intragranular porosity, increase in mean

granule size and increase in bulk density. The strength of the granules

inversely related to the intragranular porosity. Both the disintegration

time and time for 50% drug dissolution (T5oo/0) increased significantly

with increase in mixing time.

was

Lubricants, stearates in particular, are notorious for its deteriorating effect

on the crushing strength of tablets [6]. It is well known fact that excessive

blending of magnesium stearate with the dried granules leads to the

formation of poorly compacted tablets.

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Modified Starch

Worldwide, starch is one of the most widely used excipients in

pharmaceutical formulations. It is used mainly in oral solid dosage forms

as a filler, binder or disintegrant. Native starch shows poor

compressibility hence the tablets show higher friability. Next to plain

starch, a variety of chemical and physical modification techniques are

used to impart certain properties to the starches. These modified starches

are used not only in the pharmaceutical industry, but also in the textile,

glue, and paper industries. The modification techniques are often

complex and time consuming. Chemically modified starches are less

preferred in the pharmaceutical industry due to the presence of residue of

reactant/s. Kerf et al. [7] concluded that X-ray and electron beam

irradiation have an important effect on the properties of starches. The

disintegration properties of some irradiated starches were found to be

promising. The researchers warned that a careful characterization of the

irradiated products and a validation of the process are required before thisft

technique can be used as an alternative modification technique in

comparison to chemically modified starches. Considering the

disadvantages of chemical and irradiation treatment, physical

modification method was tried in the present study.

Lactose, (4-a-D-galactosido-)-D-glucose, can be obtained in two basic

isomeric crystalline forms, a and P-lactose, or as an amorphous form, a-

lactose monohydrate has been observed in a wide variety of shapes,

conditions of crystallization [8],depending on the

95

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Modified Starch

Spray-dried lactose was first reported by Gunsel and Lachman [9] in

early 1960s. The product contained about 8% amorphous material. The

spray-dried product gave harder, less friable tablets. The tablets

containing spray-dried lactose are more susceptible to color development

tollowing storage at elevated temperatures. Spray-dried lactose is

comparatively more expensive than lactose monohydrate.

Powdered a-lactose monohydrate is commonly used as filler in the

preparation of tablets by the process of wet granulation. Sieved

crystalline fractions of lactose monohydrate are widely used in direct

compression systems. Coarse crystalline fractions of a-lactose

monohydrate have very good flow property, but exhibit relatively poor

binding. This poor binding created interest in the properties of the other

types of lactose and in the application of the different lactose products in

formulations for the direct compression of tablets [6],

In spite of the rather good dry binding properties of small particles, the

poor flowability makes ground fractions of a-lactose monohydrate

unsuitable for direct compression. Sieved fractions of a-lactose

monohydrate with a proper particle size distribution, such as the 100

mesh quality, have good flow properties, but a moderate compactibility.

For this reason and because of the low price, a-lactose monohydrate 100

mesh is extensively used as a directly compressible filler-binder in

combination with excipients with good binding properties such as

microcrystalline cellulose [10]. The study underlines the importance of

and particle size distribution in direct compression.particle size

96

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Modified Starch

Spray-dried lactose was first reported by Gunsel and Lachman [9] in

early 1960s. The product contained about 8% amorphous material. The

spray-dried product gave harder, less friable tablets. The tablets

containing spray-dried lactose are more susceptible to color development

following storage at elevated temperatures. Spray-dried lactose is

comparatively more expensive than lactose monohydrate.

Powdered a-lactose monohydrate is commonly used as filler in the

preparation of tablets by the process of wet granulation. Sieved

crystalline fractions of lactose monohydrate are widely used in direct

compression systems. Coarse crystalline fractions of a-lactose

monohydrate have very good flow property, but exhibit relatively poor

binding. This poor binding created interest in the properties of the other

types of lactose and in the application of the different lactose products in

formulations for the direct compression of tablets [6],

In spite of the rather good dry binding properties of small particles, the

poor flowability makes ground fractions of a-lactose monohydrate

unsuitable for direct compression. Sieved fractions of a-lactose

monohydrate with a proper particle size distribution, such as the 100

mesh quality, have good flow properties, but a moderate compactibility.%

For this reason and because of the low price, a-lactose monohydrate 100

mesh is extensively used as a directly compressible filler-binder in

combination with excipients with good binding properties such as

microcrystalline cellulose [10]. The study underlines the importance of

and particle size distribution in direct compression.particle size

96

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Modified Starch

Cellulose is a widely used natural material. It is principally obtained from

fibrous. Spray-drying is generally used to obtain cellulose with chemical

formula (C6H10O5),,, where n has a value of 500 or more. Microcrystalline

cellulose (MCC) and powdered celluloses are available commercially.

Both powdered and microcrystalline cellulose contain the alpha cellulose

in their chemical compositions. The differences between them result from

the manufacturing process [4]. The powdered cellulose is obtained by

mechanical treatment of alpha cellulose while microcrystalline cellulose

is obtained by chemical treatment of alpha cellulose. A preliminary report

pointed the ability of MCC to form extremely hard tablets that are not

friable and yet possess unusually short disintegration time [11].

The blends of physically modified starch and MCC or lactose were tried

in the present work. The main objective was to attain economy. Lactose

monohydrate undergoes fragmentation on compression whereas starch

undergoes plastic deformation and hence it was thought worthwhile to try

a blend of lactose and starch in the present study.

The present study was undertaken to improve flow and compressional

characteristic of starch based diluents. Wet granulation was used to

develop directly compressible (physically modified starch) diluents.

Combinations of physically modified starch and MCC or lactose were

explored to investigate their effect on tablet compression and

performance.

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Modified Starch

EXPERIMENTAL

5.2. MATERIALS

The materials are described under section 3.5.

5.3. METHODS

5.3.1. Physical modification of starch

Preliminary trials were carried out using varying quantities of wheat

starch and water. Mixtures of wheat starch (3 to 5 parts) and water (5 to 7

parts) were heated at a controlled temperature (40 to 80a) in porcelain

dishes for a specified time (5 to 50 min). The porcelain dish was heated to

the required temperature for not less than 30 min before each experiment

was performed. The wet mass was subsequently passed through 44# and

dried in an oven (50-70°). The oversized granules were dried further, if

necessary and sieved as mentioned above. The 44/120 mesh fractions of

the dried granules were used for characterization. The temperature of

heating and ratio of starch to water were found to influence the

characteristics of the product and hence they were critically controlled.

5.3.2 Water solubility

Water solubility of the starches was ascertained by stirring 500 mg of the

sample with 250 ml water at 25° for 30 min and the solid content in the

aqueous phase was determined by gravimetric analysis.

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Modified Starch

5.3.3 Tableting of physically modified starch

The tablets with an average weight of 280 mg were prepared on a single

stroke tablet machine. The granules and the tablets were evaluated as

described earlier in sections 3.2 and 3.3 respectively. The results of

evaluation of the optimized batch are shown in the results and discussion

section.

5.3.4. Preparation of tablets of modified starch and MCC

A 3 full factorial design was employed to systematically investigate the

influence of adding MCC in the optimized batch of physically modified

starch. The design layout and the results of average of three observations

are shown Table 5.1. The blends of modified starch agglomerates and

MCC were lubricated using 1% talc, 1% Cab-O-Sil and 1% magnesium

stearate. The tablets were prepared on a single stroke tablet machine. The

tablets were evaluated for crushing strength, % friability and

disintegration time.

5.3.5. Preparation of tablets of modified starch and lactose

A32 full factorial design was employed to investigate the influence

adding lactose in the optimized batch of physically modified starch. The

design layout and the results are shown in results and discussion section.

The blends of modified starch agglomerates and lactose were lubricated%

using 1% talc, 1% Cab-O-Sil and 1% magnesium stearate. The tablets

prepared on a single stroke tablet machine and evaluated.were

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Modified Starch

5.4. RESULTS AND DISCUSSION

The mechanical strength of tablets is used as a quality control tool to

ensure that the prepared tablets are reproducible and can withstand the

subsequent handling procedures. In addition, the mechanical properties of

tablets are also measured to evaluate some functional properties of the

material in terms of their ability to form tablets. The method of

determining the mechanical properties is usually undertaken by the

application of a mechanical stress until the tablet breaks and recording

this value (hardness test) or by subjecting the tablets to small repeated

tumbling interaction and monitoring the loss in weight due to abrasion

(friability test). The value at which a tablet breaks is dependent on the

type of applied stress, its manner of application and the shape and

dimension of the tablet [12].

Native starch showed very poor flow and compressional characteristics.

The opening of the funnel stem was blocked by the starch powder during

the flow measurement and the tablets produced from native starch were

highly friable. The poor flow may be attributed to absorbed moisture

and/or presence of high percentage of extremely small particles. Those

who are good at the art of formulation know that native starch possess

poor compressional characteristics. One of the probable reasons may be

elastic recovery on ejection of a tablet from die.

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Modified Starch

5.4.1. Physically modified starch

The granules of the optimized batch of the physically modified starch

showed acceptable percentage compressibility (9.73%), Hauser ratio (1.1)

and angle of repose (30°). The preferable values for these parameters are

shown in earlier chapters. The improved characteristics of the processed

starch may be attributed to agglomeration of starch particles. The particle

size distribution of the native starch and modified starch (optimized

batch) is shown in Fig. 5.1. The crushing strength, disintegration time and

friability of the tablets of the optimized batch were found to be 5 kg, 36

sec and 0.88 % respectively. The temperature of heating and ratio of

wheat starch to water were found to influence the characteristics of the

product and hence they shall be critically controlled. It is a known fact

that if the temperature of heating is more than the gelatinization

temperature of starch, gelatinization and rupture of starch grains will

occur. The tablets containing substantial amount of gelatinized starch will

show slower water uptake and delayed disintegration due to gel

formation. If the temperature of heating is well below the gelatinization

temperature of starch the characteristics of starch are not suitably

modified. The gelatinization temperature of wheat starch is 58° and

hence the temperature was varied around 60" in the present study. The

used during the modification procedure determines theamount of water

quantity of leached materials from starch. The leached materials cause

transformation of particles into granules. Hence, quantity of water shall

also be critically controlled. Native starch contained <0.1% water soluble$

optimized batch of the physically modified starchfraction whereas the

contained 11% water soluble fraction. On incorporation of any poorly

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Modified Starch

compressible drug in the physically modified starch, the crushing strength

of the tablets will decrease below 5 kg. Friability of the drug containing

tablets is expected to be greater than normally acceptable value of 1%.

Another major disadvantage of the tablets containing substantial amountS

of starch is the dull appearance. Such tablets may show poor patient

compliance. Moreover, the manufacturer will find it difficult to capture a

larger market share due to dull appearance of the tablets. Formulation and

development scientists in the Indian pharmaceutical industry are currently

concentrating research on cost optimization. The cost of starch is much

lower as compared with that of MCC or lactose. One of the reasons of

undertaking the present work is to achieve cost reduction by substituting

a part of MCC or lactose with starch. Blends of the physically modified

starch agglomerates and either MCC or lactose were prepared in order to

further improve the functionality of the diluents.

ZI Native Starch

0 Modified StarchFigure 5.1:Histogram of Native and Modified

Starch

60

50

"2 40m////..9 £5%

30am\HHi20

eV/-

O10

m1 io

30-60 60-72 72-100 100-120 120-400 >400

Sieve number (#)

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Modified Starch

5.4.2. Factorial design

A 3 full factorial design was adopted using the amount of physically

modified starch (Xi) and lactose or MCC (X2) as independent variables.

The design layout and the results of % friability, disintegration time and

crushing strength of the tablets are shown in Table 5.1.

Table 5.1: Design Layout and Results of Measured Responses

Lactose (X2)MCC (X2)

X, XT Friability DT Crushing Friability DT* Crushingl 2

strengthstrength

(%) (Sec) (Kg)

-1 -1 <0.5 36

-1 0 < 0.5 44

-1 1 <0.5 50

0 -1 <0.5 29

0 0 <0.5 34

0 1 <0.5 44

1 -1 <0.5 24

1 0 <0.5 29

1 1 <0.5

Variable

Amount of modified starch (Xi)

Amount of lactose or MCC (X2)

*nT=Disinteuration time

(%) (Sec) (Kg)

4.8191.539

4.7211.6610

5.0212.0211

5.0191.367

4.75161.579

4.7211.6610

5.0201.117

5.0191.368

4.8191.53936

Low(-l) Medium (0) High (1)

50 70 90

10 30 50

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Modified Starch

5.4.3 Blend of physically modified starch and MCC

The cmshing strength of the tablets ranged from 7 to 11 kg. The increase

in crushing strength indicates that the selected response is dependent on

the independent variables, i.e. the amount of starch and MCC. Linear

regression analysis was carried out to evolve mathematical models. The

full and the reduced models are shown in Table 5.2.

Table 5.2: Results of Regression Analysis---— - --------- --1.-i. „ -T v .»!— .

___~~ ~ rr-- .TV.— -r-zrs-.-------:-:--—---—•-

MCC (X2)Coefficient Lactose (X2)

Crushing Disintegration Friability Disintegration

Timestrength

Intercept 8.67 (8.77)+ 36.22(35.11) (1.526) (17.88)

-0.67(-1.0) -6.82 (-6.83) (-0.201) (-0.5*)

(0.5*)

(1.16)

(0.005) (1.16)

(-0.0175) (-0.75)

(0.7272)

Time— —

X I

0.83 (1.16) 6.83 (6.83) (0.201)

* (0.33) * (0.83) (0.005)

*(-0.16) *(0.83)

*(0.0) *(0.51)

* (0.9849) * (0.9952

X22X1

2X2

X!X2

R+

Xi = Starch, ' Values in the parenthesis indicates the full model

R = Correlation coefficient, *(p > 0.05)IL_ rTX

The results of multiple linear regression analysis reveal that both the main

effects are statistically significant (P<0.05). From the reduced model, it

can be concluded that the cmshing strength of the tablets can be increased

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Modified Starch

by increasing the concentration of MCC in the blend. The increase in

crushing strength is probably attributed to good compaction

characteristics of MCC as compared to that of starch. It is well known

fact that MCC also exhibits binding effect. Hence, it is concluded that the

blends of physically modified starch and MCC shall be preferred by the

formulators. The crushing strength of the tablet is inversely related with

the amount of starch. This conclusion is drawn from the fact the

coefficient attached with starch carries a negative sign (-0.67). We can

draw the above mentioned conclusions, without going for further data

analysis, since the interaction and the polynomial terms are insignificant

(P>0.05). The response surface plot is shown as Figure 5.2.

Figure 5.2: Response Surface plot for Crushing Strength(Starch+MCC)

ne 12

AC/53* 11c9 10(JO

W 9

89(JO 7 50

X* 56 407? 60:(JO

% 3070 cc°4m 20 *80

90 10

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Modified Starch

The contour plot is shown as Figure 5.3. The user can identify an area

that will give the acceptable crushing strength. The final selection is to be

made after considering the other points such as friability, disintegration

time, cost, etc. Dry blending of MCC with starch is preferred as

compared to wet processing since MCC loses a part of its compressibility

on wet granulation. Effect plot is shown in Figure 5.4 for the formulators

who intend to extract information from the results without going in for

complex statistical analysis.

“1

Figure 5.3: Contour Plot for Crushing Strength

(Starch + MCC)

10.8 100.60.40.2 H 9

0X-0.2-0.4

8-0.6-0.8

-1 —r I—-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

Xi

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Modified

Figure 5.4: Effect Plot for Crushing Strength

(Starch+MCC)

12 i

1o-111

X!

CIO4=

in 9WDc

8cnSs 7U

6 J

1-1 0Starch

Friability

Friability all the tablets containing starch and MCC was found to be <0.5

% (Table 5.1). It is concluded from the results that inclusion of MCC in

the modified starch resulted in substantial reduction of friability of the

tablets. Since the difference in percentage friability between batches was

very less, regression analysis was not carried out. It is worthwhile to note

that microcrystalline cellulose is used by formulators due to its superior

compressibility. The improvement in % friability may be attributed to

increase in crushing strength of the tablets.

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Modified Starch

Disintegration time

The disintegration time ranged from 24 to 50 sec, which indicates that the

selected response is dependent on the independent variables, i.e. the

amount of starch and MCC. The full and the reduced models are shown in

Table 5.2. The results of multiple linear regression analysis reveal that

both the main effects are statistically significant (P<0.05). The results are

shown in the form of response surface plot and contour plot in Figure 5.5

and 5.6 respectively.

Figure 5.5: Response surface plot for Disintegration Time(Starch+MCQ

O55&

50

45tic•n /Si 40

35©s

30

25320

50&

60ft>40a

70 30

80 cv20NV

90 10%

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Modified Starch

Figure 5.6: Contour Plot for Disintegration

l ime (Starch + M(

10.8 450.60.4 400.2

N 0 - 35-0.2-0.4 30

-0.625

-0.8-1 rT

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

X i

The conclusions made under crushing strength are also applicable to

disintegration time since the reduced model contains the same significant

terms. The marginal increase in disintegration time may be due to

increase in crushing strength. The pharmaceutical formulators know that

both starch and MCC acts as disintegrant and hence the tablets

disintegrated in less than 1 min. Figure 5.7 shows the effect plot. The

contour plots shown in Figure 5.3 and 5.6 may be overlapped and the user

may identify an area of interest, e.g. crushing strength of the tablets less

than 8 kg and disintegration time less than 30 sec (Figure 5.8). Friability

of the tablets within the factor space is expected to be less than 0.5%.

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Modified Starch

Figure 5.7: Effect plot for Disintegration Time

(Starch+MCC)

55

10-150<uS 45HB 40 H

CJat 35 'u C/5

8P 30 -aGO

25520 4

-1 10

Starch

Figure 5.8: Combined Contour Plot for

Modified Starch

1 DH;4Cs(10) 45)0.8 Cs(9)

0.611(35)

0.40.2 Cs(8)n

0 H

-0.2 1(30) i

-0.4-0.6 DT(25)

-0.8-1 —

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

Xi

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Modified Starch

A novel data mining technique is proposed, wherein the user need not be

well-versed with computers and statistics. The proposed method is

suitable for designs with two variables. It is assumed that linearity exists

in the data and the interaction and polynomial terms are insignificant. The

transformed values of factors Xi and X2 are to be entered by the user (See

Table 5.3). The experimental values of crushing strength are then entered

in respective cells in the ExcelR worksheet (entries made in cells with

yellow background). Linear interpolation was adopted to calculate the

data in the remaining cells. The steps are shown below Table 5.3. In order

to evaluate the efficiency of the proposed methods, a similar matrix

(Table 5.4) was generated using the reduced model shown in Table 5.2.

The sum of the squares of the residuals and the percentage deviation are

shown in Tables 5.5 and 5.6. The results reveal that the proposed method

showed reasonable estimate of the response, i.e. crushing strength. The

maximum percentage difference is less than 10%. The method is well

suited for the research scientists working in the pharmaceutical industry

since they have to complete the formulation development work in a

defined time frame. Academician should adopt the classical approach of

linear regression analysis. It must be remembered that the proposed

method is based on a number of assumptions before any conclusions are

drawn. The simplicity and the speed are the two main advantage of the

proposed method.

Ill

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Modified Starch

j%

Table 5.3: Data Matrix and Steps for Generating Intermediate

Values

ABC JIE F G HDV>

10.5 -0.25 0 0.25 0.5 0.75

10.25 10.5 ' 10.75

L -0.75 8.5 8.8125 9.125 9.4375 9.75 10 10.25 10.5 10.75

8.375 8.75 9.125 9.5 9.75 10 10.25 10.5

-0.25 7.5 7.9375 8.375 8.8125 9.25 9.5 9.75 10 10.25

-0.75

-1•y

4 9.25 9.5 9.75 »

1*1-0.5

0 9.25 9.5 9.75

0.25 7 7.4375 7.875 8.3125 8.75 9 9.25 9.5 9.75

7.5 8 8.5

0.5 7.375 7.75 8.125 8.5 8.75 9 9.25 9.5K— •

- » —I 8.25 8.5 8.757.25 7.5 7.75 i

Transformed levels of MCC- Row No. 1

Transformed levels of Starch - Column A

Data entered in red colour in the cells with yellow backgroundStep 1 .I \ \

Mean of data shown in yellow background in a columns-B, F and JStep 2

Mean of data shown in yellow background in a row- next step -Step 3mm

f

Data obtained in blue colour shows average of two

8.5 observations in columns B, D, F, H and JStep 4

Average value generated by taking two values in a rowStep 5

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Modified

Table 5.4: Computed values of Crushing Strength - Reduced model

0.75 1-0.250.75 -0.5

8.61 8.9 9.19 9.48 9.77 10.06 10.35 10.64 10.93

1 0.0

-1

-0.75 8.36 8.65 8.94 9.23 9.52 9.81 10.1 10.39 10.68

-0.5 8.11 8.4 8.69 8.98 9.27 9.56 9.85 10.14 10.43

-0.25 7.86 8.15 8.44 8.73 9.02 9.31 9.6 9.89 10.18

0 7.61 7.9 8.19 8.48 8.77 9.06 9.35 9.64 9.93

0.25 7.36 7.65 7.94 8.23 8.52 8.81 9.1 9.39 9.68

0.5 7.11 7.4 7.69 7.98 8.27 8.56 8.85 9.14 9.43

0.75 6.86 7.15 7.44 7.73 8.02 8.31 8.6 8.89 9.18

1 6.61 6.9 7.19 7.48 7.77 8.06 8.35 8.64 8.93

Table 5.5: Data Matrix for Sum of Squares of Residuals-

1 -0.75 -0.5 -0.25 0 0.25 0.5 0.75 1

-1 0.152 0.123 0.096 0.073 0.053 0.036 0.023 0.012 0.005

-0.75 0.020 0.026 0.034 0.043 0.053 0.036 0.023 0.012 0.005

-0.5 0.012 0.001 0.004 0.021 0.053 0.036 0.023 0.012 0.005

-0.25 0.130 0.045 0.004 0.007 0.053 0.036 0.023 0.012 0.005

0.372 0.160 0.036 0.000 0.053 0.036 0.023 0.012 0.005

0.25 0.130 0.045 0.004 0.007 0.053 0.036 0.023 0.012 0.005

0.012 0.001 0.004 0.021 0.053 0.036 0.023 0.012 0.005

0.75 0.020 0.026 0.034 0.043 0.053 0.036 0.023 0.012 0.005t

0.152 0.123 0.096 0.073 0.053 0.036 0.023 0.012 0.005

0

0.5

1

113I

*

l

1 (122)

Modified Starch

Table 5.6: Matrix for Absolute Percentage Difference

-1 -0.75 -0.5 -0.25 0 0.25 0.5 0.75 11j

| -1 4.3 3.78 3.26 2.77 2.30 1.85 1.43 1.02 0.64I

-0.75 1.6 1.84 2.03 2.20 2.36 1.90 1.46 1.05 0.65

-0.5 1.4 0.30 0.69 1.59 2.42 1.95 1.50 1.07 0.67

-0.25 4.8 2.68 0.78 0.94 2.49 2.00 1.54 1.10 0.68

8.7 5.33 2.37 0.24 2.56 2.05 1.58 1.13 0.70

0.25 5.1 2.86 0.83 0.99 2.63 2.11 1.62 1.16 0.72

0.5 1.6 0.34 0.77 1.78 2.71 2.17 1.67 1.19 0.74

0.75 2.0 2.22 2.43 2.61 2.79 2.24 1.71 1.22 0.76

1 5.6 4.83 4.13 3.48 2.88 2.30 1.76 1.26 0.78

0

Note: Absolute % difference = Difference between proposed and

classical method

5.4.4 BLEND OF PHYSICALLY MODIFIED STARCH AND

LACTOSE

Crushing strength

The crushing strength of the tablets ranged from 4.5 to 5 (Table 5.1). The

difference in the crushing strength between different batches was slight

enough for them to be considered for further data analysis.

Friability

The value of friability of the tablets ranged from 1.11 to 2.02 (Table 5.14

and Figure 5.9), which indicates that the selected response is dependent

the amount of starch and lactose. The results of multiple linear

regression analysis reveal that both the main effects are statistically

on

114

1 (123)

Modified Starch

significant (P<0.05). It can be concluded that the friability of the tablets

depends on the percentage lactose present in the blend. The coefficient

associated with factor X2 carries a positive sign, i.e. as the amount of

starch increases in the blend, the friability of the tablet increases. We can

draw these conclusions, without going for further data analysis since the

interaction and the polynomial terms are insignificant (P>0.05).

Figure 5.9: Response surface plot of % Friabilty

(Starch+Lactose)

© 2o

SBO’

5014060

3070

H 2080 ASPVten 90 10

St<*4

The reduced model is shown in the form of contour plot in Figure 5.10

and the effect plot is shown in Figure 5.11. The results reveal that

incorporation of Prismalac 40R in the modified starch, unacceptable

on

115

1 (124)

*

»

Modified Starch

Rtablets (friability >1%) were obtained. Friability of the Prismalac 40

tablets was found to be >1.

]Figure 5.10: Contour Plot for % Fribility forj

(Starch + Lactose)

1s'

1.80.8

0.6 s *

0.4 1.6 >

0.2

X 0 »

1.4-0.2 %

-0.4

-0.6•sr

1.2-0.8 /.

-1

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 I

X,

Figure 5.11:Effect plot for % Friability

(Starch+Lactose)

2.2 -1-1 0

2

£>1.8x 1.6•s-bm:14e

1.2

10 1-1

Starch

116I

*

1

1 (125)

Modified

Disintegration time

The disintegration time of the tablets ranged from 16 to 21 sec (Table

5.1). The narrow range demonstrates that the disintegration time of the

tablets is hardly affected by changing amount of starch and lactose.

Modified starch itself is a good disintegration agent and hence

insignificant effect was noticed on inclusion of lactose.

disintegration time may be attributed to lower crushing strength of the

tablets as compared to the tablets containing starch and MCC. Lactose, a

water-soluble diluent, provides pores on dissolution and hence faster

uptake of the liquid medium may be expected from the tablets containing

lactose and starch.

The lower

Starch and MCC blend yielded superior tablets as compared with that of

starch and lactose and hence it was selected for dilution potential study.

Dilution potential study of the blend containing 90% starch and 10%

MCC as diluent reveal that upto 30% of nimesulide can be incorporated

in it. The crushing strength and friability of the tablets were found to be 5

kg and 0.67% respectively.

5.5. CONCLUSIONS

Physically modified starch agglomerate seems to be a suitable directly%

compressible diluent for potent compressible drugs. The friability of the• i

tablets was found to be close to the upper acceptable limit for uncoated

1%. The blend of agglomerated starch and MCC showed verytablets, i.e.

low % of friability (<0.5) and high crushing strength. The blend of

117

1 (126)

Modified Starch

physically modified starch and lactose was not found to be beneficiary

since the value of crushing strength remained less than or equal to 5 Kg

and friability >1%. If Prismalc 40R is considered as a poorly compressible

model material, we may conclude that a large percentage of it should not

be mixed with the modified starch. The systematic formulation approach

enabled us to develop acceptable tablets. Finally, it is concluded that

batches containing modified starch and MCC serve as good direct

compressible agent considering low value of friability, disintegration time

and acceptable crushing strength. It

large percentage of poorly compressible drugs. Mouth dissolve tablets

be developed for pediatric and geriatric patients using the directly

can

accommodate a comparativelycan

can

compressible agents.

5.6. REFERENCES

1. Sam A. P. and Fokkens J. G., Pharm. Tech. Eur., 1997, 9, 58.

2. Chowhan Z. T, Pharm. Tech., 1993, 17, 72.

3. Seager H., Rue P. J., Burt I., Ryder J. and Warrrack J. K., Int. J.

Pharm. Tech & Prod. Mfr., 1981, 2, 41.

4. Opata D., Prinderre P., Kaloustian J., Joachim G., Piccerelle P.

Ebba F., Reynier J. P. and Joachim J., Dmg Develop. Ind. Pharm.,

1999, 25, 795.

5. Chalmers A. A. and Elworthy P. H., J. Pharm. Pharmacol., 1976,

82, 239.

6. Lerk C. F., Drug Develop. Ind. Pharm., 1993, 19, 2359.

7. De Kerk M., Mondelaers W., Lahorte P., Vervaet C. and Remon J./

P., Int. J. Pharm., 2001, 221, 69.

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1 (127)

Modified Starch

8. Zeng X. M., Martin G. P., Marriott C. and Prichard J., J. Pharm.

Pharmcol., 2000, 52, 633.

9. Gunsel W. C. and Lachman L., J. Pharm. Sci., 1963, 52, 178.

lO.Bolhuis G. K. and Zuurman K., Dmg Develop. Ind. Pharm., 1995,

21,2057.

1l.Fox C. D., Richman M. D., Reier G. E. and Shangraw R. F., Drugs

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12.Newton J. M., Haririan I., Podezeck F., Eur. J. Pharm. and

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119