Curr. Pharm. Res. 2019, 9(3), 3002-3019

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Current Pharma Research ISSN-2230-7842

CODEN-CPRUE6

www.jcpronline.in/

Research Article

Development of Multifunctional Directly Compressible Co-processed Orodispersible

Excipient Using Spray Drying Technique.

Chetan Borkhataria*, Ritesh Gurjar, Jayant Chavda, Ravi Manek, Kaplesh Patel,

Dhavalkumar Patel

B. K. Mody Govt Pharmacy College, Rajkot, Gujarat, India.

Received 23 January 2019; received in revised form 31 January 2019; accepted 31 January

2019

*Corresponding author E-mail address: chetanborkhataria@gmail.com

ABSTRACT

To develop an attractive formulation platform for the continuous production of directly

compressible powders. This could have improved compressibility and compatibility, containing

poorly compressible drug substance. Powder mixtures containing mannitol, MCC, Kyron T-314,

maltodextrin, aerosil® 200 and neotame were Co-processed. A 10.0%w/v feed suspension was

selected for process optimization. Preliminary optimization determined the optimal spray drying

process (inlet temperature: 150°C, outlet temperature: 140°C, feed flow rate: 3 ml/min, aspiration

rate: 50 Nm3/hr, atomization pressure: 1.5 bar). Adequate regression models developed after

constructing D-optimal mixture design. The optimized formulation (mannitol: 49.5%w/w, MCC:

20%w/w, Kyron T-314: 10%w/w) found to be having a disintegration time of 13.2±0.08 sec and

dilution potential up to 50%. Spray drying offers precise control over particle size and forms

porous agglomerates suitable for direct compression, an advantage over melt granulation. The

use of maltodextrin, MCC and mannitol in mixtures resulted in high process yields. Spray dried

mixtures containing mannitol were non-hygroscopic with good flowability. MCC provides a

free-flowing highly compressible powder. Kyron T-314 found to be excellent disintegrant.

Maltodextrin provides appropriate tablet tensile strength. By incorporating systematic

formulation approach, a novel excipient can be developed having improved compressibility,

compatibility, flowability and reduced disintegration time.

KEYWORDS

Co-processed excipient, Spray drying, Direct compression, Mannitol, Kyron T-314,

microcrystalline cellulose.

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1. INTRODUCTION

The term co-processing refers to processing two or more established excipients by appropriate

means to provide synergy of functionality. Flowability, compressibility and compactability as

well as masking undesirable properties of individual excipient are few functions. Elimination of

wet granulation production stages, avoidance of keeping and handling various excipients as well

as the synergetic effect of having homogenous free flowing directly compressible formulation of

the required excipients cause them to interact at the subparticle level and lead to superior

properties than simple physical mixtures of their components.[1-4]

Among different co-processing techniques; spray drying is an attractive single step process(i.e. a

fully continuous manufacturing process without granulation, milling and/or blending steps in

between spray drying and compaction, improving production efficiency and reducing costs) to

develop dry and homogenous agglomerate powder. Improved flowability and compactability are

because of precise control over particle size as well as forms porous agglomerates. This is due to

higher inlet temperature and increased surface area during droplet formation which are suitable as

directly compressible adjuvant.[4-8] Spray drying is a technique which can be easily automated,

equipped for in-line product analysis thus reducing time-to-market because of scale-up benefits

and better quality which offers many economic benefits for a pharmaceutical processing.[3,5,9]

Advantageous commercially available Co-processed excipients with reduced number of

incorporated excipients are Compressol S (multifunctional property), Ludipress (improved

flowability, low hygroscopicity and tablet hardness independent of machine speed), prosolv

(Improved compressibility, lesser fill weight variation and reduced lubricant sensitivity),

cellactose (good disintegration property, better dilution potential), Pharmatose DCL 40(better

dilution potential) and Avicel CE15 (Improved organoleptic properties), Ludiflash or Parteck

(good disintegration property, satisfactory disintegration properties).[4,10]

It was found that a Co-processed mixture of α-lactose monohydrate and maize starch showed a

better flowability, higher tablet tensile strength and faster tablet disintegration. Heckel analysis

proved that the spray dried mixture deformed plastically with limited elasticity. The physical

mixture exhibited a predominantly elastic behavior in powder.[11] Rojas J et al.,(2012)

concluded that SDCII`(spray dried cellulose II) is less friable, less sensitive to magnesium

stearate, and possessed better acetaminophen loading capacity than unprocessed cellulose II

which is comparable to cellulose I.[12] Jacob S et al.,(2007) developed novel co-processed

excipients of mannitol and microcrystalline cellulose(MCC) for preparing fast dissolving tablets

of glipizide by spray drying process. This study revealed that co-processed formulation

containing mannitol and MCC in the ratio of 1.25:1 have optimized powder and compressibility

characteristics with fast disintegrating property.[13]

Gonnissen et al.,(2007) have formulated co-spray dried ternary drug/carbohydrate mixture

containing mannitol, erythritol, maltodextrin and acetaminophen concluding that erythritol and

maltodextrin fractions improves powder flowability and tensile strength respectively with

improved compactability of acetaminophen.[5]

In the present study protocol an attempt made to optimize the ratio of different excipients and to

design multifunctional directly compressible co-processed orodispersible excipient having higher

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compressibility, flow property, dilution potential and lower disintegration time(DT) using poorly

compressible drug (e.g. cefuroxime axetil (CA)) as model drug.

2. MATERIALS AND METHODS

2.1. Materials

Cefuroxime axetil was obtained as gift sample from Unimark remedies Ltd., (Ahmedabad,

India). Mannitol and MCC were purchased from S D Fine Chem Limited (Mumbai, India).

Kyron T-314 was obtained from Corel Pharma Chem (Ahmedabad, India). Maltodextrin was

obtained as gift sample from Gujarat Ambuja Exports Ltd (Ahmedabad, India). Neotame and

aerosil® 200 was purchased from Axal laboratoreies and Chemdyes Corporation (Rajkot, India),

respectively.

2.2. Methods

2.2.1. Preparation of spray dried Co-processed excipient:

Based on preliminary study excipients with appropriate proportion were selected. The selection

was on bases of their specific characteristics and functionality. The material characteristics like

plastic, elastic or brittle material, chemical and physical properties, cost, and availability are

considered.[4] The materials were dispersed in aqueous system to make 10% w/v slurry followed

by homogenized mixing to form uniform dispersion.[14] The slurry concentration was made

fixed at 10% w/v as it was appropriate with spray drying process variables. Spray drying of

aqueous dispersion containing fixed concentration of maltodextrin (15% w/w), neotame (5%

w/w), aerosil® 200 (0.5% w/w) and variable concentration of mannitol, MCC and Kyron T-314

was performed in a lab-scale spray dryer (LU-222 Advanced, Labultima Ltd., Mumbai). The

contents of the variable excipients in the formulations are listed in Table 1. The spray dryer was

operated in co-current airflow with process condition maintained as shown in Table 2. The feed

dispersion was pumped through an atomization gun equipped with a fluid nozzle tip (0.7 mm),

which generates fine droplets in the upper part of the drying chamber. Inlet temperature was

maintained always above 100° C because of water as the solvent. The spray mechanism is

formed by internal mix of the slurry and compressed air. The hot drying air is passed through the

nozzle, meets the droplets, drying them into particles, and enables the dried particles to have

short residence times in the drying chamber and in the cyclone. The dried particles trapped in the

cyclone are then collected in the product reservoir.[4,5,7,14]

Table 1. Variable excipients composition of total 15 runs.

RUN Actual values (79.5%)* Coded values

X1

(Mannitol)

X2

(Kyron

T-314)

X3

(MCC)

X1

(Mannitol)

X2

(Kyron

T-314)

X3

(MCC)

1 47.83 15 16.67 0.32 -0.33 -0.33

2 44.5 25 10 0.13 1 -1

3 38 25 16.5 -0.25 1 -0.35

4 39.5 10 30 -0.16 -1 1

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5 38.7 18.9 21.9 -0.21 0.19 0.19

6 44.5 25 10 0.13 1 -1

7 39.5 10 30 -0.16 -1 1

8 31.5 25 23 -0.62 1 0.3

9 49.5 10 20 0.42 -1 0

10 59.5 10 10 1 -1 -1

11 59.5 10 10 1 -1 -1

12 52 17.5 10 0.57 0 -1

13 25 24.75 29.75 -1 0.97 0.98

14 32.25 17.25 30 -0.58 -0.03 1

15 39.1 14.45 25.95 -0.18 -0.41 0.6

*The experimental design variable components contain 79.5% w/w proportion of total solid

content as well as fixed proportions of maltodextrin (15% w/w), neotame (5% w/w) and aerosil®

200 (0.5% w/w).

Table 2. System process conditions during spray drying by labscale spray dryer (LU 222

Advanced)

System process

parameters

Settings

Inlet air temperature 150˚C

Outlet air temperature 140˚C

Feed flow rate 3 ml/min

Aspiration rate 50 Nm3/hr

Atomization pressure 1.5 bar

2.2.2. Experimental design

Data from a preliminary study were used to construct the mixture design. Mannitol was used

because of its positive effects on powder flowability and compactability observed.

Microcrystalline cellulose was added to improve flowability and disintegration. Kyron T-314

was incorporated to obtain rapid disintegration. The mannitol content varied between 25% and

59.5%w/w, while the MCC and Kyron T-314 fractions were changed from 10% to 30% w/w and

from 10% to 25% w/w, respectively. The lower content limit of MCC was chosen to realize its

effect on DT its maximum content was limited to avoid a strong negative influence on tablet

flowability. A content of maltodextrin was fixed at 15% w/w to achieve appropriate tensile

strength.

A D-optimal mixture design was selected because interactions between the variables were

expected.[15] The following full cubic model (Equation 1) was proposed:

Y=β˳+β1X1+β2X2+β3X3+β12X12+β13X13+β23X23+β11X11+β22X22+β33X33+β123X123…..…….(1)

Where, Y: response

β˳: overall coefficient (intercept)

β1, β2, β3: Co-efficient of X1, X2, X3 variables

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β12, β23, β13, β123: Co-efficient of interaction

β11, β22, β33: Co-efficient of quadratic terms

X1, X2, X3: Independent variables

The candidate points were chosen by the software (Design-Expert version 6.0.8, Stat-Ease,

Minneapolis, USA) were: vertices (4), centers of the edges (4), thirds of the edges (8), check

points (4), interior blends (4), overall centroid (1), constraint plane centroid(1) and Triple

blends(4). From the 30 candidate points, 11 runs chosen to establish the model, 4 runs for

measuring the lack-of-fit generating 15 runs. Manual multiple linear regression was performed.

The different responses chosen were Carr’s index, Hausner ratio, angle of repose, tablet tensile

strength, DT and percentage process yield.

2.3. Evaluation of spray dried Co-processed excipient

2.3.1. Angle of Repose

Angle of repose was studied by the fixed funnel method with 2cm height between tip of funnel

and ground. The material is poured through a funnel to form a cone. The tip of the funnel should

be held close to the growing cone and slowly raised as the pile grows, to minimize the impact of

falling particles. The samples were graded as per scale of flowability (Table 3). [16,17]

2.3.2. Carr’s index

The percentage compressibility (Carr’s index) was calculated as 100 times the ratio of the

difference between tapped density and bulk density to the tapped density, which were graded as

per scale of flowability (Table 3).[18,19]

2.3.3. Hausner ratio

Hausner ratio is the ratio of tapped density to bulk density. It is measure of the propensity of

powder to be compressed. Lower the value of Hausner ratio better is the flow property (Table 3).

Table 3. Scale of flowability.

Flow character Carr’s index Hausner

ratio

Angle of repose

(°)

Excellent ≤ 10 1.00 – 1.11 25 – 30

Good 11-15 1.12 -1.18 31 – 35

Fair (aid not needed) 16-20 1.19 – 1.25 36 – 40

Passable (may hang up) 21-25 1.26 – 1.34 41 – 45

Poor (must

agitate/vibrate)

26-31 1.35 – 1.45 46 – 55

Very poor 32-37 1.46 – 1.59 56 – 65

Very very poor > 38 > 1.60 > 66

2.3.4. Kawakita’s and Kuno’s equation

The packability was evaluated using Kawakita’s (Equation 2, 3, 4)(Kawakita K and Ludde K

1970-71) and Kuno’s equation (Equation 5)(Niwa T, Takeuchi H et al. 1994) by tapping the

agglomerates in a measuring cylinder. 𝑛

𝑐=

1

𝑎𝑏 +

𝑛

𝑎 …………………………...………………..….(2)

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𝑎 = 𝑉0−𝑉𝑖𝑛𝑓

𝑉0 …………………………..…………..........(3)

𝑐 = 𝑉0−𝑉𝑛

𝑉0…………………..….…………………..…..……(4)

Where a and b are constants, n is the tap number, Vo, Vn, and Vinf are the powder bed volumes

initially, after the nth

tapping and at equilibrium, respectively.

𝜌𝑓 − 𝜌𝑛 = 𝜌𝑓 − 𝜌0 𝑒(−𝑘𝑛 )………………………….…….(5)

Where ρo, ρn, and ρf, are the apparent densities initially, after the nth

tapping (5, 10, 15, 20, 25,

50, 75, 100, 200, 300, and 400) and at equilibrium (500th

tap) respectively, and k is a constant.

2.3.5. Heckel analysis

A Heckel plot allows the interpretation of the mechanism of compression based on the

assumption that powder compression follows first-order kinetics, with the interparticulate pores

as the reactant and the compactability of the powder bed as the product. The compressibility

behavior of the co-processed excipient of optimized batch and physical mixture having the same

composition were studied. Co-processed excipient (500 ± 5 mg) was compressed in a hydraulic

press and matching die at pressures of 1, 2, 3, 4, 5, 6 and 7 tons for 1 min and compacts were

stored over silica-gel for 24 hour (to allow elastic recovery, hardening and prevent falsely low

yield values). The weight, diameter and thickness of the compacts were determined. The data

was processed using the Heckel equation (Equation 6) and the mean yield pressure (Py) from the

reciprocal of k was obtained by regression analysis of the linear portion of the plot.[20,21]

ln 1

1−𝐷 = 𝑃𝑘 + 𝐴……………………………………….(6)

Where D is the relative density of a powder compact at pressure P. Slope k is a measure of the

plasticity of a compacted material. Constant A is related to the die filling and particle

rearrangement before deformation and bonding of the discrete particles.

2.4. Post-compression parameters

2.4.1. Dilution Potential

The dilution potential is the amount of poorly compressible drug that can be satisfactorily

compressed into a tablet with a directly compressible excipient. The tablets containing different

drug: excipients blend ratios were prepared and were evaluated for angle of repose and DT.[16]

2.4.2. Tensile Strength

The dimensions of the tablets were measured using a micrometer. The crushing strength was

determined after 24 hr (time for stress relaxation) of compression, using a hardness tester. From

the values of the diameter (D, cm), thickness (L, cm) and crushing strength (P, kg), the tensile

strength (MPa) of the tablets was calculated using Equation 7.[22]

𝑇 = 2×𝑃

𝜋 × 𝐷 × 𝐿 ……..……………………………………………....(7)

2.4.3. Friability

Friability was evaluated from percentage weight loss of 20 tablets tumbled in a friabilator at

25±1 rpm for 100 rpm. The tablets were then de-dusted, and the loss in weight caused by fracture

or abrasion was recorded as percentage weight loss.

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2.4.4. Weight uniformity test

Individually 20 units selected at random, weighed and average weight was calculated. Not more

than two of the individual weights deviate from the average weight by more than the percentage

limit and none deviates by more than twice of that percentage.

2.4.5. Disintegration Time

The DT was measured using a modified disintegration method (n = 5). For this purpose, a

petridish (6.5cm diameter) was filled with 10 ml of water. The tablet was carefully put in the

center of the petridish and the time for the tablet to completely disintegrate into fine particles was

noted.[23]

2.4.6. Wetting time

Wetting time is closely related to the inner structure of the tablets and to the hydrophilicity of the

excipient. It is obvious that pores size becomes smaller and wetting time increases with an

increase in compression force or a decrease in porosity. A linear relationship exists between

wetting time and DT. To illustrate wetting of the tablet, a piece of tissue paper folded twice was

placed in a petridish (internal diameter 6.7cm) with 10 ml of water containing a water-soluble

dye. A tablet was carefully placed on the surface of tissue paper and the time required for water

to reach upper surface of tablet was noted as wetting time that indicates complete wetting of

tablets.[24,25]

2.4.7. In-vitro dispersion time

In vitro dispersion time was measured by dropping a tablet in a measuring cylinder containing 6

ml of simulated salivary fluid (Phosphate buffer pH 6.8) to ensure disintegration of tablets in the

salivary fluid.[26]

2.4.8. In-vitro Dissolution Study:

In-vitro dissolution study of tablet was carried out in 0.1 N HCl (900 ml, 37 ± 0.5˚C) by using

USP 24 paddle apparatus (50 rpm). Samples (5 ml) were withdrawn at predetermined time

intervals, filtered through Whatman filter paper, and assayed at about 278 nm (λmax of CA) by

using UV-Vis spectrophotometer to determine the percentage drug released.

3. RESULTS AND DISCUSSION

3.1 Pre compression parameters

Table 4. Pre-compression parameters

Run Carr's

index

Hausner

ratio

Angle of

repose (°)

Disintegration

time (sec)

Tensile

strength(MPa)

Percentage

yield

1 16.66 1.194 27.596 19 0.749 60.64

2 15.21 1.188 23.21 50 0.718 83.55

3 17.64 1.213 24.601 38 0.63 75.47

4 6.77 1.078 24.8344 29 0.693 85.77

5 15.9 1.189 27.254 31 0.652 70.16

6 13.33 1.149 22.524 58 0.735 86.55

7 9.83 1.108 25.109 32 0.662 83.77

8 20.37 1.244 25.2576 27 0.587 72.74

9 10.63 1.107 23.179 9 0.78 76.14

10 14.28 1.18 20.932 10 0.842 74.51

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11 14.28 1.162 21.256 9 0.828 71.51

12 17.94 1.212 26.234 34 0.79 68.1

13 18.91 1.242 27.362 22 0.571 61.24

14 19.29 1.249 29.253 38 0.596 54.31

15 13.88 1.166 27.146 27 0.66 73.74

3.1.1 Carr’s index (percentage compressibility)

From Table 4, it can be concluded that powder agglomerates of all runs exhibited excellent to

fair flow (Carr’s index ranging from 6.77 to 20.37). Generally, lower the value of Carr’s index is

preferable. As increase in proportion of X1(mannitol) and X3(MCC) there was decrease in

Carr’s index value i.e. increase in percentage compressibility.

To get insight into the factors that play role in controlling percentage compressibility, multiple

linear regressions were performed and the polynomial equation (Equation 7) was derived by

using results data.

Carr’s index = -276.292 - 20208*X1 - 8740.25*X2 - 11770.7*X3 + 2900.3*X12 - 3873.42*X13

+ 1257.761*X22 – 2245.21*X33 + 1.550834*X123 …………….……..... (7)

From the results of multiple regression analysis, it can be observed that factors X2, X3 and X1

increases in ascending fashion with negative sign, i.e., a unit change in percentage of Kyron T-

314, MCC and mannitol will bring in change in Carr’s index in decreasing order (runs 4, 10, 13,

6). The polynomial equation confirmed the conclusion that the mannitol and MCC have inverse

effect on Carr’s index. The proportion of Kyron T-314(X22) attained positive sign, indicated that

as proportion of Kyron T-314 increase there is substantially increase in Carr’s index (runs 3, 8,

13). It is worthwhile to note that at constant concentration of X2(Kyron T-314), X1(mannitol)

and X3(MCC) factors have reciprocal effect on Carr’s index (runs 3, 7, 9). As the proportion of

X3 (MCC) increases, subsequently there is decrease in Carr’s index value i.e. increase in

compressibility (runs 4, 7). At constant X3(MCC) concentration as increase in proportion of X1

(mannitol) causes decrease in Carr’s index i.e. increase in compressibility behavior of powder

(runs 4, 7). It can be concluded that by co-processing of the powder mixture having combination

of excipients having specific functionality characteristics, there was increase in compressibility

characteristics of formulated Co-processed powder.

Figure 1. SEM of Co-processed excipient at 1800 Magnification

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Figure 2. SEM of Co-processed excipient at 4700 Magnification

Here, mannitol and MCC are plastic materials and maltodextrin is brittle in nature, the Co-

processed powder developed having the combination of both characteristics, which can be seen

in scanning electron microscopy (SEM) of the developed excipient (Figure 1 & 2). It was

concluded that the mannitol and MCC increases the compressibility and compactability of

powder excipient.[5]

3.1.2 Hausner ratio

From Table 4, it can be concluded that powder agglomerates of all runs exhibited excellent to

good flow (Hausner ratio from 1.078 to 1.249). Lower value of for Hausner ratio is preferred. As

with increasing the proportion of X1(mannitol) and X3(MCC) there was decrease in Hausner

ratio, in other words there was increase in compressibility.

Hausner’s ratio = - 2.23193 - 236.47*X1 - 102.742*X2 - 137.086*X3 + 0.873127*X12 -

1.25406*X13 + 0.333692*X22 - 0.71193*X33 + 0.030009*X123.… (8)

From equation 8, increase in proportion of X2(Kyron T-314) has positive effect (run 3, 8) on

Hausner ratio while increase in X3(MCC) proportion results in inverse effect (run 4, 7) on

Hausner ratio i.e. increase in flow property and compressibility. At constant X3 (MCC), increase

in proportion of X1 and X2 results in higher Hausner ratio (run 12, 14). On other side, increase

in proportion of X1(mannitol) and X3(MCC) having inverse effect i.e. lower value of Hausner

ratio. Therefore, it can be concluded that mannitol and MCC have significant effect on Hausner

ratio i.e. ultimately on the flow property and compressibility of powder.

3.1.3 Angle of repose (AOR) (°)

AOR is measure of flow properties of developed spray dried powder mixtures. From results

obtained (Table 4), it can be concluded that powder agglomerates of all runs exhibited excellent

flow property. The values of AOR are ranging from 20.93° and 29.25°. The improved flow

property may be due to Co-processed agglomerates having uniform particle size (Figure 1-2).

Hence, it can be concluded that any of these combination among all runs shown in Table 1 yields

acceptable flow.

Angle of repose = -70.0601 - 6724.89*X1 - 2938.59*X2 - 3876.64*X3 - 1047.22*X12 +

1396.086*X13 - 458.954*X22 + 809.3775*X33 - 1.13731*X123 …. (9)

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Equation 9 revealed that factors X2, X3 and X1 increases in ascending fashion with negative

sign, i.e. a unit change in percentage of Kyron T-314, MCC and mannitol will bring change in

AOR in decreasing order (runs 6, 9, 10). It was seen that with increasing concentration of

mannitol there is increase in the flowability of powder. The equation confirmed that formulations

containing mannitol had good flowability which is also supported by the study carried out by

Gonnissen et al. (2007).[5] The term X2 (Kyron T-314) has negative effect on AOR, i.e. as

increasing X2 proportion there is decrease in AOR (runs 3, 6). An increasing concentration of

X3 (MCC) there was increase in AOR i.e. decrease in flowability (run 14). Microscopy revealed

that the MCC is fibrous in nature. The fluidity of MCC is poor compared to that of most of other

direct-compression fillers because of its relatively small particle size and fibrous shape.[4]

3.1.4 Disintegration time

DT exhibited by all batches was below 1 min. The probable reasons for quicker disintegration

attributed to the presence of super disintegrant, i.e., Kyron T-314 as well as presence of MCC.

The DT found to be lowered at lower proportions of MCC and Kyron T-314. When results of DT

(Table 4) treated for multiple linear regression results were found confirming to the above

discussion.

Disintegration time = 287.19294 + 7899.817*X1+108.307*X2+9960.88*X3+1526.02*X12-

28670.4*X13 + 9352.584*X22- 6612.2*X33+8.351702*X123 ... (10)

Equation 10 revealed that as decrease in the proportions of X2 (Kyron T-314) as well as X3

(MCC), there was decrease in DT (run 10 and 11). At constant proportion of X2 (Kyron T-314),

with increasing concentration of X3 (MCC), there was decrease in the DT (run 2, 3, 6 and 8). At

constant X2 (Kyron T-314), as increasing the proportion of both X1 and X3 factors, results in

decrease in DT (run 8, 9 and 11). At constant X3(MCC) concentration, with increasing

proportions of X1 and X2 results in increase in DT (run 2, 6, 12 and 14) that can be also

supported by Equation 13. It was also seen that the effect of square of X3 (MCC) results in

increase in DT (run 7, 4, 14). From SEM analysis it can be concluded that after spray drying the

MCC powder shape converted from fibrous to oblong (Figure 1-2) and the improved DT is due

to wicking action by MCC and swelling action by Kyron T-314.

3.1.5 Tensile strength

Tensile strength was found to be satisfactory for all runs (from 0.571 to 0.842 MPa). Equation 11

revealed that factors X2, X3 and X1 showed positive effect in increasing order, i.e., a unit

change in percentage of Kyron T-314, MCC and mannitol will bring in change in tensile strength

in increasing order (runs 4, 10, 12).

Tensile strength = 2.292 + 110.701*X1 + 47.876*X2 + 64.297*X3 – 11.590*X12 + 15.452*X13

– 5.030*X22 + 8.967*X33 -0.0534X123 ………………… (11)

The increase in proportion of the X1 (mannitol) and X2 (Kyron T-314) at fixed X3 (MCC)

concentration, resulted in decreased tensile strength (run 2, 6, 12). As the amount of

X1(mannitol) and X3 (MCC) increased at constant X2 level (Kyron T-314), the tensile strength

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of Co-processed powder was also increased. At the same time effect of square of X2 (Kyron T-

314) and X3 (MCC), results in decreased (run 2, 6) and increased (run 8, 13, 14) tensile strength

value, respectively. Thus, from the equation 11 it can be concluded that the tensile strength is

positively affected mainly by two factors X1 (mannitol) and X3 (MCC).

3.1.6 Percentage yield

The results (Table 4) showed that percentage yield range for all runs were from 54.31 % to

86.55%.

Percentage yield = 854.2011 + 54308.67*X1 + 23550.59*X2 + 31561.41*X3-4163.89*X12 +

5572.059*X13 - 1798.37*X22 + 3228.387*X33 + 3.17306*X123……………….. (12)

From equation 12, as unit increase in proportion of X1 (mannitol), X2 (Kyron T-314) and X3

(MCC), there is increase in percentage yield (run 2, 4, 7, 6, 10). At higher proportion of X2 the

percentage yield was going to be decreased (run 8) while at the higher proportions of X3 (MCC)

the percentage yield was found to be higher (run 4). It was also seen that at constant proportion

of X3 (MCC), increase in proportion of both the terms X1 and X2 results in decrease in

percentage yield value (run 12, 14). While on other side, at constant proportion of X2 (Kyron T-

314), increasing proportions of X1 and X3 resulted in increase in percentage yield (run 4,

7).Therefore, it can be concluded that mannitol and MCC have positive effect on percentage

yield.

3.2 Selection of optimized composition

After data analyzed by multiple linear regression analysis, the polynomial equation was obtained

from the coefficient values of each independent variable and interaction term. From polynomial

equations, predicted values were obtained for each response upon analyzing total 756 runs. All

the observed results of measured responses were within prediction intervals and in good

agreement with predicted results. Therefore, among them 12 runs were sorted out based on the

appropriate required range of responses as shown in Table 5.

Table 5. Predicted results of R1-R12

Run X1

(mannitol)

X2

(Kyron

T-314)

X3

(MCC)

Carr’s

index

Hausner

ratio

Angle of

repose(°)

Disintegration

time (sec)

Tensile

strength

(Mpa)

Percentage

yield

R1 0.57 0.00 -1.00 17.3504 1.2047 26.2090 34.2967 0.7941 65.7472

R2 0.32 -0.33 -0.33 17.1828 1.1951 26.9428 20.3244 0.7401 63.5932

R3 -0.21 0.19 0.19 16.5991 1.2010 27.4471 30.4027 0.6571 68.2607

R4 1.00 -1.00 -1.00 16.1097 1.1861 21.5203 8.0341 0.8292 69.7586

R5 0.13 -0.33 0.00 14.4161 1.1646 26.6861 22.7151 0.7205 70.3676

R6 -0.18 -0.41 0.60 13.9890 1.1694 27.4937 27.4210 0.6656 70.1077

R7 0.13 1.00 -1.00 13.8707 1.1576 22.4790 57.7485 0.7291 87.9407

R8 0.42 -1.00 0.00 10.4862 1.1006 23.5425 7.5629 0.7786 78.2577

R9 -1.00 0.97 0.98 18.8217 1.2474 27.2171 22.0441 0.5730 61.3303

R10 -0.58 0.00 0.98 18.0171 1.2351 29.2461 35.7954 0.5924 60.3903

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Run R8 was ranked as the best run considering the lowest value of DT (7.56 sec), as well as

lower value of Carr’s index and Hausner’s ratio i.e. 10.486 and 1.107, respectively. Run R8 also

having higher value for tensile strength and percentage yield of 0.779 MPa and 78.26 %,

respectively. It can be seen that value for angle of repose (°) was in range of excellent scale of

flowability i.e. 23.54°. Therefore, depending on the results run R8 was decided as the optimized

run giving best results in required appropriate ranges.

3.3 Characterization of optimized run excipient

After optimization of data, the run R8 was formulated and results obtained for optimized run R8

with their respected responses are as shown in Table 6.

Table 6. Evaluation parameters for optimized batch R8.

Run Carr’s

index

Hausner’s

ratio

Angle of

repose (°)

Disintegration

time (sec)

Tensile

strength(Mpa)

Percentage

yield (%)

R8 10.83 1.1090 22.2840° 9 0.747 79.14

3.3.1 Dilution Potential

To check the dilution potential of developed multifunctional directly compressible Co-processed

orodispersible excipient, the optimized run i.e. R8 was selected. Tablets were prepared with

cefuroxime axetil proportion ranging from 10% to 50%. The results obtained for angle of repose

(°) and DT (sec) are shown in Table 7.

Table 7. Results for dilution potential of run R8.

Dilution

(%)

Angle of

repose (°)

Disintegration

time (sec)

0 23.179 9

10 23.184 10

20 23.998 13

30 24.83 16

40 25.56 22

50 25.988 34

The obtained results were analyzed by t-test for testing the significance of a single mean

(Equation 16).

𝑡 = 𝑛 ( 𝑋− 𝜇 )

𝑆……………………………………….……………..…… (13)

Where n=sample size, X=sample mean, µ=predicted value, S=standard deviation of sample

Table 8. t-test parameters.

Term Angle of

repose (°)

Disintegration

time (sec)

Sample size (n) 5

R11 -0.25 1.00 -0.35 17.5363 1.2115 24.1846 37.6402 0.6342 77.8106

R12 -0.16 -1.00 1.00 9.7115 1.1075 25.0559 32.8750 0.6711 80.2595

Curr. Pharm. Res. 2019, 9(3), 3002-3019

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Mean (X) 24.712 19

Standard deviation

(SD)

1.140809 9.486833

t- test (calculated) 2.293284 2.695727

t- test (tabulated) ((n—

1)/α)

2.78

Upon comparing the population (pure excipient) mean with sample mean (excipient diluted with

drug), it was clearly observed that tcalculated < ttabulated indicating insignificant difference between

pure excipient and batches containing combination with respect to physical parameters in Table

8.

3.3.2 Kawakita’s and Kuno’s equation

Table 9. Kawakita's parameters in equation

Tap

number

(n)

n/c

Mannitol MCC Physical

mixture

Run R8

125.00 250.00 125.00 125.00

10 125.00 125.00 125.00 125.00

15 187.50 125.00 187.50 187.50

20 166.67 125.00 166.67 166.67

25 156.25 125.00 208.33 156.25

50 250.00 208.33 312.50 250.00

75 375.00 312.50 468.75 312.50

100 416.67 357.14 500.00 416.67

200 714.29 714.29 833.33 833.33

300 1000.00 1071.43 1153.85 1250.00

400 1333.33 1428.57 1538.46 1666.67

500 1666.67 1785.71 1923.08 2083.33

The packability was ascertained by comparing the constants a, b, and k in Kawakita’s and

Kuno’s equations, respectively. The constant a represents the proportion of consolidation as

closest packing is attained. The reciprocal of b and k represents the packing velocity. The

parameters for Kawakita’s equation are sown in Table 9.

Curr. Pharm. Res. 2019, 9(3), 3002-3019

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Figure 3.1 Kawakita's plot.

Table 10. Kwakita and kuno's parameters in equation

Test Kawakita's Kuno's

a b k

Run R8 0.252 0.058 0.018

Physical mixture

(run R8)

0.281 0.029 0.029

MCC 0.298 0.044 0.032

Mannitol 0.325 0.029 0.037

The constant for the run R8 (0.252) was smaller than for mannitol (0.325) and MCC powder

(0.298) (Table 10). This result indicated that the agglomerates of run R8 having good packing

even without tapping. The larger b value of the run R8 (0.058) proved that the packing velocity

of the agglomerated powder (run R8) was faster than that of mannitol and MCC powder (Figure

3). The smaller value of k in Kuno’s equation supports the above findings (Table 10). The slow

packing velocity corresponds to the proportion of the consolidation of the powder bed per tap.

Because of improved packability, agglomerates of run R8 showed improved compression

compared with mannitol and MCC powder.

3.3.3 Heckel analysis

Table 11. Results for Heckel analysis.

Pressure

(Tons)

ln (1/1-D)

Mannitol MCC Physical

mixture

Run

R8

1 0.6684 0.6642 0.6984 0.5679

2 1.0875 0.7490 0.8451 0.8898

3 1.6020 1.6564 1.8128 1.1996

0

500

1000

1500

2000

2500

0 200 400 600

n/c

Tap number (n)

Kawakita's plot

Mannitol

MCC

Physical mixture

Run R8

Curr. Pharm. Res. 2019, 9(3), 3002-3019

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4 1.8638 1.9400 2.1964 1.4426

5 1.9256 2.1418 2.2991 1.9256

6 1.9807 2.1864 2.3516 1.9807

7 2.0618 2.2656 2.4657 2.0618

Figure 4. Heckel plot.

Table 12. Heckel parameters in equation.

Test sample a k Py

Run R8 0.2639 0.3827 2.613013

Physical mixture

(run R8)

0.5526 0.3143 3.181674

MCC 0.4913 0.2916 3.429355

Mannitol 0.6999 0.2247 4.450378

The results (Table 11) obtained over a range of compression pressures from 1–7 tons were

analyzed by the Heckel equation. The yield pressure (Py) was calculated from the reciprocal of

the slope k of the regression line (Figure 4). According to Heckel, the linear part of the curve

describes the plastic deformation of the material and elastic deformation is considered negligible.

It was also concluded that, at low pressure, the curved region of the plot is associated with

individual particle movement in the absence of interparticle bonding, and that the transition from

curved to linear corresponds to the minimum pressure necessary to obtain a coherent pressure.

The agglomerates, which had lower values, undergo plastic deformation because of the

rebonding of primary crystals smaller than those of the original powder. Mannitol and MCC

mainly undergo plastic deformation. The Py value reflects the compression characteristics of the

material. The lower Py value, the greater is plastic deformation (run R8 having lowest 2.613).

From the data shown in Table 12, it can be concluded that run R8 exhibited plastic deformation

due to the presence of mannitol with MCC.

3.4 Evaluation of tablet containing model drug

3.4.1 Post compression parameters

0.000

0.500

1.000

1.500

2.000

2.500

3.000

0 5 10

ln (

1/1

-D)

Pressure (Tons)

Heckel plot

Mannitol

MCC

Physical mixture

Run R8

Curr. Pharm. Res. 2019, 9(3), 3002-3019

3017

The prepared tablets were evaluated for post compression physical parameters such as hardness,

weight variation, and friability, wetting time, in-vitro dispersion time and DT. Percentage weight

variation was observed between 2.4 ± 0.63%, within the acceptable limit for uncoated tablet as

per IP 2010. The hardness was found to be 3.6±0.14 kg/cm2. Friability indicating sufficient

mechanical integrity and strength was observed 0.62±0.29 % which was below 1% of the

prepared tablets. Wetting time is closely related to the inner structure of the tablets and the

hydrophilicity of the excipients determined as 9.2±0.34 seconds. In-vitro dispersion time was

found to be 12.9±0.12 seconds. Much important DT was found to be 13.2±0.08 seconds for

formulated tablets; it was also observed that the tablets with the least wetting time showed

minimum DT evident a strong correlation between wetting time and DT. In-vitro drug

dissolution studies showed maximum drug release of 82.73% at end of 15 min.

4. CONCLUSION

A co-processed multifunctional directly compressible Co-processed orodispersible excipient was

prepared in this present investigation by spray drying technique, which is potential attractive

alternative. Regression models developed for Carr’s index, Hausner ratio, angle of repose, tensile

strength, DT and percentage yield. Optimization was applied to determine the optimal contents

for mannitol (49.5% w/w), Kyron T-314 (10% w/w) and MCC (20% w/w). The Carr’s index was

more influenced by mannitol and MCC. On other hand, the DT was influenced by Kyron T-314

and MCC. Mannitol influenced compactibility, flowability and tensile strength of powder while

Kyron T-314 and MCC minimized tablet DT. MCC also have influence on flowability.

Maltodextrin have potential effect on tablet tensile strength. Up to 50% cefuroxime axetil,

proportion was incorporated in the optimized run R8 excipient for successful formulation of

tablets by direct compression. Spray drying offers precise control over particle size and forms

porous agglomerates suitable for direct compression, an advantage over melt granulation. In the

end, it is concluded that by incorporating systematic formulation approach, a novel excipient

containing mannitol (plastic), MCC (plastic), maltodextrin (brittle), Kyron T-314, colloidal

silicon dioxide and neotame can be developed which is successful in improving compressibility,

compactibility, flowability with reduce DT.

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