**3. Methodology for powder characterization by SeDeM-ODT expert system**

To determine the suitability of powder/powder blend for direct compression and bucco-dispersibility, SeDeM-ODT expert system needs 15 parameters to be found out. The individual parameters of SeDeM-ODT expert system are determined according to their respective pharmacopoeial methods, reported methods, or calculation on the basis of other basic parameters.

Characterization of powder according to the SeDeM-ODT expert system [11, 14] involves the following:


### **3.1 Determination/calculation of basic parameters of SeDeM-ODT expert system**

SeDeM-ODT expert system is based on 15 basic parameters [14] which are determined experimentally or calculated on the basis of other included parameters. Procedures for the determination of basic parameters are given below:

#### *3.1.1 Bulk density*

• Drying of material to reduce its loss on drying.

*2.1.5 Lubricity/dosage factor*

*Advanced Functional Materials*

• Homogeneity index

in this factor are as follows: • Effervescence test

• Disintegration time with disk

Compressibility Inter-particle

*D. time with disk: Disintegration time with disk. D. time without disk: Disintegration time without disk. \*Experimental; The parameter was determined experimentally.*

Flow ability/powder

flow

**Table 1.**

**170**

porosity

• Disintegration time without disk

*2.1.6 Disgregability*

and comprised of the following:

• Particles having size below 50 μm

• Product should be processed in a controlled environment at low humidity.

Parameters included in this factor affect the lubricity and dosage of the tablet

Parameters included in disgregability factor govern disintegration behavior of the final product and are specified for fast dispersible tablets. Parameters included

**Incidence factor Parameter Symbol Unit Equation Limits Applied factor** Dimension Bulk density Da g/mL Da = P/Va 0–1 10 V

Carr's index Ic % 100 (Dc–Da)/

Lubricity/stability Loss on drying %HR % Experimental 0–10 10 – V

Lubricity/dosage Particles <50 %Pf % Experimental 0–50 10 – (V/5) Homogeneity index I*Ѳ* — *Fm/100 + ΔFmn* 0–2

Disgregability Effervescence time DE Min Experimental 0–5 (5 – V) 2

*Basic parameters of SeDeM-ODT expert system divided into different incidence factors.*

Tapped density Dc g/mL Dc = P/Vc 0–1 10 V

Cohesion index Icd N \*Experimental 0–200 V/20

Hausner ratio IH — Dc/Da 3–1 (30–10 V)/2 Angle of repose (α) o tan<sup>1</sup> (h/r) 0–50 10 – (V/5) Powder flow t″ S Experimental 0–20 10 – (V/2)

Hygroscopicity %H % Experimental 0–20 10 – (V/2)

D. time with disk DCD Min Experimental 0–3 (3 – V) 3.333 D. time without disk DSD Min Experimental 0–3 (3 – V) 3.333

Da

Dc

0–1.2 10 V/1.2

0–50 V/5

10<sup>2</sup>

500 V

Ie — Dc – Da/Dc

Bulk density of the powder substance is determined according to the USP using graduated cylinder method [16]. The volume of the weighed amount of powder is determined using a graduated cylinder, and the density is calculated using the following equation:

$$D = \frac{m}{V} \tag{1}$$

where D is the density of the powder (g/mL), m is the weight of the powder (g), and v is the volume of the powder (mL).

#### *3.1.2 Tapped density*

Tapped density of powdered material is determined according to the USP by tapping known volume of powder taken in a graduated cylinder and noting the volume reduction [16]. Tapping can be carried out manually or using mechanical tappers.

#### *3.1.3 Inter-particle porosity*

Values of bulk density and tapped density are used for the calculation of interparticle porosity [17], using the following equation:

$$\text{Le} = \frac{\text{Dc} - \text{Da}}{\text{Dc} \ge \text{Da}} \tag{2}$$

<sup>∝</sup> <sup>¼</sup> tan �<sup>1</sup> <sup>H</sup>

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical…*

by powder (cm), and r is the radius of the base of cone formed by powder (cm).

Powder flow is determined, in accordance with the European Pharmacopeia, by measuring the time required for the powder (100 g) to flow through the orifice of a

Loss on drying is determined gravimetrically according to the USP [20], using a halogen moisture analyzer. The powder (1 g) is loaded into the pan of moisture analyzer and heated for specified time at 100°C, and the value of percent loss is

Hygroscopicity is measured by placing the accurately weighed amount of powder in a climatic chamber at 75 � 5% relative humidity for 24 h at ambient temperature. The material is analyzed after 24 h for percent weight gain by reweighing

Sieve shaker fitted with standard sieves of pore size 850, 600, 425, 300, and 250 μm is used for the determination of particle size distribution. The powder (100 g) is loaded on the top sieve and the sieve shaker is vibrated for 10 min. The

Homogeneity index is determined according to the European Pharmacopoeia [21]. The powder (100 g) is loaded to a sieve shaker fitted with sieves of 850, 500, 425, 300, 250, and 50 μm pore size, and the sieve shaker is vibrated for 10 min. The percent amount of powder retained over each sieve and that passed through a 50 μm sieve is calculated. Homogeneity index of the material is calculated using the

<sup>I</sup><sup>θ</sup> <sup>¼</sup> Fm

where Iθ is the relative homogeneity index and Fm is the percentage of particles

If the percentage is higher than that calculated in the complete sieve test, it is because some of the particles become adhered to the product retained in the sieves during the grain size test, and the percentage of particles below 50 μm particles found may be lower than the true figure. The following equation (Eq. (7)) is then

<sup>100</sup> <sup>þ</sup> <sup>Δ</sup>Fmn (6)

percent amount of the powder retained over each mesh is calculated [21].

where α is the angle of repose of powder (<sup>o</sup>

glass funnel fitted at certain height [19].

*DOI: http://dx.doi.org/10.5772/intechopen.92444*

*3.1.8 Powder flow*

*3.1.9 Loss on drying*

*3.1.10 Hygroscopicity*

[13], indicating its hygroscopicity.

*3.1.11 Particle size distribution*

*3.1.12 Homogeneity index*

equation mentioned below:

in the majority range.

**173**

applied to the data obtained.

noted.

r

(5)

), H is the height of the cone formed

where Ie is the inter-particle porosity, Dc is the tapped density (g/mL), and Da is the bulk density (g/mL).

#### *3.1.4 Carr's index*

Carr's index is calculated on the basis of tapped density and bulk density of powder [16]:

$$\text{C.I.} = \frac{\text{Dc} - \text{Da}}{\text{Dc}} \ge 100 \tag{3}$$

where C.I. is the Carr's index of the powder (%), Dc is the tapped density of the powder (g/mL), and Da is the bulk density of the powder (g/mL).

#### *3.1.5 Cohesion index*

Cohesion index is the crushing strength of powder compressed, preferably in an eccentric press under maximum pressure without capping and lamination [11]. The mean crushing strength is calculated for at least 10 compacts, indicating the cohesion index of the powder. The raw powder is tested for compressibility, and in case of failure, 3.5% of the following mixture is added to the mix:


#### *3.1.6 Hausner ratio*

Hausner ratio is calculated from bulk density and tapped density of powder [16] according the equation given below:

$$\text{Hr} = \frac{\text{Dc}}{\text{Da}}\tag{4}$$

where Hr is the Hausner ratio of the powder, Dc is the tapped density of the powder (g/mL), and Da is the bulk density of the powder (g/mL).

#### *3.1.7 Angle of repose*

Angle of repose is determined by funnel method [18]. The test powder is allowed to flow from a glass funnel fitted at certain height, and angle of repose was determined using the equation:

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical… DOI: http://dx.doi.org/10.5772/intechopen.92444*

$$\infty = \tan^{-1} \left( \frac{\text{H}}{\text{r}} \right) \tag{5}$$

where α is the angle of repose of powder (<sup>o</sup> ), H is the height of the cone formed by powder (cm), and r is the radius of the base of cone formed by powder (cm).

#### *3.1.8 Powder flow*

*3.1.3 Inter-particle porosity*

*Advanced Functional Materials*

the bulk density (g/mL).

*3.1.4 Carr's index*

*3.1.5 Cohesion index*

• Talc 2.36%

*3.1.6 Hausner ratio*

*3.1.7 Angle of repose*

**172**

mined using the equation:

• Aerosil® 200 0.14%

• Magnesium stearate 1.00%

according the equation given below:

powder [16]:

particle porosity [17], using the following equation:

Values of bulk density and tapped density are used for the calculation of inter-

Ie <sup>¼</sup> Dc � Da

Carr's index is calculated on the basis of tapped density and bulk density of

where C.I. is the Carr's index of the powder (%), Dc is the tapped density of the

Cohesion index is the crushing strength of powder compressed, preferably in an eccentric press under maximum pressure without capping and lamination [11]. The mean crushing strength is calculated for at least 10 compacts, indicating the cohesion index of the powder. The raw powder is tested for compressibility, and in case

Hausner ratio is calculated from bulk density and tapped density of powder [16]

Hr <sup>¼</sup> Dc

where Hr is the Hausner ratio of the powder, Dc is the tapped density of the

Angle of repose is determined by funnel method [18]. The test powder is allowed to flow from a glass funnel fitted at certain height, and angle of repose was deter-

powder (g/mL), and Da is the bulk density of the powder (g/mL).

<sup>C</sup>*:*I*:* <sup>¼</sup> Dc � Da

powder (g/mL), and Da is the bulk density of the powder (g/mL).

of failure, 3.5% of the following mixture is added to the mix:

where Ie is the inter-particle porosity, Dc is the tapped density (g/mL), and Da is

Dc x Da (2)

Dc x 100 (3)

Da (4)

Powder flow is determined, in accordance with the European Pharmacopeia, by measuring the time required for the powder (100 g) to flow through the orifice of a glass funnel fitted at certain height [19].

#### *3.1.9 Loss on drying*

Loss on drying is determined gravimetrically according to the USP [20], using a halogen moisture analyzer. The powder (1 g) is loaded into the pan of moisture analyzer and heated for specified time at 100°C, and the value of percent loss is noted.

#### *3.1.10 Hygroscopicity*

Hygroscopicity is measured by placing the accurately weighed amount of powder in a climatic chamber at 75 � 5% relative humidity for 24 h at ambient temperature. The material is analyzed after 24 h for percent weight gain by reweighing [13], indicating its hygroscopicity.

#### *3.1.11 Particle size distribution*

Sieve shaker fitted with standard sieves of pore size 850, 600, 425, 300, and 250 μm is used for the determination of particle size distribution. The powder (100 g) is loaded on the top sieve and the sieve shaker is vibrated for 10 min. The percent amount of the powder retained over each mesh is calculated [21].

#### *3.1.12 Homogeneity index*

Homogeneity index is determined according to the European Pharmacopoeia [21]. The powder (100 g) is loaded to a sieve shaker fitted with sieves of 850, 500, 425, 300, 250, and 50 μm pore size, and the sieve shaker is vibrated for 10 min. The percent amount of powder retained over each sieve and that passed through a 50 μm sieve is calculated. Homogeneity index of the material is calculated using the equation mentioned below:

$$\text{I}\theta = \frac{\text{Fm}}{\text{100} + \Delta \text{Fmn}} \tag{6}$$

where Iθ is the relative homogeneity index and Fm is the percentage of particles in the majority range.

If the percentage is higher than that calculated in the complete sieve test, it is because some of the particles become adhered to the product retained in the sieves during the grain size test, and the percentage of particles below 50 μm particles found may be lower than the true figure. The following equation (Eq. (7)) is then applied to the data obtained.

$$\begin{array}{l} \text{I\(\theta = F\mathbf{m}/100 + (\text{dm} - \text{dm} - 1)\,\text{Fm} - 1 + (\text{dm} + 1 - \text{dm})\,\text{Fm} + 1 \\ \quad + (\text{dm} - \text{dm} - \text{dm} - 2)\,\text{Fm} - 2 + (\text{dm} + 2 - \text{dm})\,\text{Fm} + 2 + \dots \\ \quad + (\text{dm} - \text{dm} - \text{dm} - \text{n})\,\text{Fm} - \text{n} + (\text{dm} + \text{n} - \text{dm})\,\text{Fm} + \text{n} \end{array} \tag{7}$$

where Iθ is the relative homogeneity index and particle size homogeneity in the range of the fractions studied; Fm is the percentage of particles in the majority range; Fm � 1 is the percentage of particles in the range immediately below the majority range; Fm + 1 is the percentage of particles in the range immediately above the majority range; n is the order number of the fraction studied under a series, with respect to the major fraction; dm is the diameter of the particles in the major fraction; dm � 1 is the mean diameter of the particles in the fraction of the range immediately below the majority range; and dm + 1 is the mean diameter of the particles in the fraction of the range immediately above the majority range.

The major fraction (Fm) corresponds to the interval from 0.100 to 0.212 mm, because it falls in the middle of the other fractions of the table. This interval is calculated as the proportion in which the powder particles are found in each fraction considered in the table (as described above). Those particles located in the major fraction (Fm) in a proportion of 60% are considered to represent the minimum acceptable value of 5. The distributions of the other particles are considered to be Gaussian. The limits for the homogeneity index are set between 0 and 0.02.

> experimental determination or calculations of various parameters are converted to "r" values by applying specific factors, representing radii of the diagram. The diagram is formed by connecting radius values with linear segment [13], having 0 as a minimum value, 10 as maximum value, and 5 as minimum acceptable value as shown in **Figure 1**. The resultant diagram indicates suitability of the material to be

*Diagrammatic presentation of (A) SeDeM-ODT and (B) SeDeM expert system. Da, bulk density; %HR, loss on drying; dc, tapped density; %H, hygroscopicity; Ie, inter-particle porosity; %Pf, particle size; IC, Carr's index; Iθ, homogeneity index; ICd, cohesion index; DE, effervescence test; IH, Hausner ratio; DCD, disintegration time with disk; Α, angle of repose; DSD, disintegration time without disk; t , flow ability.*

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical…*

Optimum mechanical strength, disintegration behavior, and rheological charac-

Parametric index is the ratio of number of parameters having "r" values equal to or greater than 5 to the total number of parameters determined during the study.

<sup>I</sup>*:*<sup>P</sup> <sup>¼</sup> No*:*P≥<sup>5</sup>

where I.P. is the parametric index, No. P ≥ 5 is the number of parameters with "r" values equal to or more than 5, and No. Pt is the total number of parameters

Parameter profile index is the average of "r" values of all the parameters deter-

mined in the study, and its acceptable limit corresponds to a score of 5.

No*:*Pt (8)

teristics of powder are estimated on the basis of the following indices [11, 14]

compressed by direct compression.

*DOI: http://dx.doi.org/10.5772/intechopen.92444*

**3.3 Calculation of various indices**

*3.3.1 Parametric index*

**Figure 1.**

determined.

**175**

*3.3.2 Parameter profile index*

calculated using "r" values of the basic parameters.

Parametric index was calculated using the following equation:

Acceptability limit corresponds to a score of 5.

IPP = Average of "r" value of all parameters

#### *3.1.13 Effervescence time*

Effervescence test for powder compact is determined as per official monograph [22]. The powder is compressed into tablets under maximum pressure without any capping and lamination. One tablet is placed in a beaker containing 200 mL of purified water at ambient temperature. Time taken by the tablet to disperse completely is taken as its effervescence time. Tablet is said to be dispersed completely when there is no agglomerate of the particles. In the context of SeDeM expert system, effervescence does not mean conventional acid-base reaction rather refers to dispersion of the compact in water. Effervescence time is an indicator for oro-dispersible tablets. When tablet disaggregates in less than 5 min, it is considered suitable for oral disintegration.

#### *3.1.14 Disintegration time with disk*

The powder is compressed under maximum pressure without any capping or lamination and subjected to the determination of disintegration time using USP disintegration apparatus. Disintegration time with disk is determined for at least six tablets, using de-ionized water as a medium held at 37 � 2°C [23], and their mean is calculated (n = 6).

#### *3.1.15 Disintegration time without disk*

Disintegration time is determined as described in the previous section without any disk [23].

All the basic parameters of SeDeM-ODT expert system, along with symbols, units, and acceptable limits, are listed in **Table 1**.

#### **3.2 Conversion of experimental values (V) to radius values (r) and graphical presentation of results**

Results of SeDeM-ODT expert system are graphically presented as SeDeM-ODT diagram built on the basis of basic parameters. Values obtained from the

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical… DOI: http://dx.doi.org/10.5772/intechopen.92444*

#### **Figure 1.**

Iθ ¼ Fm*=*100 þ ð Þ dm � dm � 1 Fm � 1 þ ð Þ dm þ 1 � dm Fm þ 1 þ ð Þ dm � dm � dm � 2 Fm � 2 þ ð Þ dm þ 2 � dm Fm þ 2 þ …

þ ð Þ dm � dm � dm � n Fm � n þ ð Þ dm þ n � dm Fm þ n (7)

where Iθ is the relative homogeneity index and particle size homogeneity in the range of the fractions studied; Fm is the percentage of particles in the majority range; Fm � 1 is the percentage of particles in the range immediately below the majority range; Fm + 1 is the percentage of particles in the range immediately above the majority range; n is the order number of the fraction studied under a series, with respect to the major fraction; dm is the diameter of the particles in the major fraction; dm � 1 is the mean diameter of the particles in the fraction of the range immediately below the majority range; and dm + 1 is the mean diameter of the particles in the fraction of the range immediately above the majority range.

The major fraction (Fm) corresponds to the interval from 0.100 to 0.212 mm, because it falls in the middle of the other fractions of the table. This interval is calculated as the proportion in which the powder particles are found in each fraction considered in the table (as described above). Those particles located in the major fraction (Fm) in a proportion of 60% are considered to represent the minimum acceptable value of 5. The distributions of the other particles are considered to be Gaussian. The limits for the homogeneity index are set between 0 and 0.02.

Effervescence test for powder compact is determined as per official monograph [22]. The powder is compressed into tablets under maximum pressure without any capping and lamination. One tablet is placed in a beaker containing 200 mL of purified water at ambient temperature. Time taken by the tablet to disperse completely is taken as its effervescence time. Tablet is said to be dispersed completely when there is no agglomerate of the particles. In the context of SeDeM expert system, effervescence does not mean conventional acid-base reaction rather refers to dispersion of the compact in water. Effervescence time is an indicator for oro-dispersible tablets. When tablet disaggregates in less than 5 min, it is considered suitable for oral disintegration.

The powder is compressed under maximum pressure without any capping or lamination and subjected to the determination of disintegration time using USP disintegration apparatus. Disintegration time with disk is determined for at least six tablets, using de-ionized water as a medium held at 37 � 2°C [23], and their mean is calculated

Disintegration time is determined as described in the previous section without

All the basic parameters of SeDeM-ODT expert system, along with symbols,

**3.2 Conversion of experimental values (V) to radius values (r) and graphical**

diagram built on the basis of basic parameters. Values obtained from the

Results of SeDeM-ODT expert system are graphically presented as SeDeM-ODT

*3.1.13 Effervescence time*

*Advanced Functional Materials*

*3.1.14 Disintegration time with disk*

*3.1.15 Disintegration time without disk*

**presentation of results**

units, and acceptable limits, are listed in **Table 1**.

(n = 6).

**174**

any disk [23].

*Diagrammatic presentation of (A) SeDeM-ODT and (B) SeDeM expert system. Da, bulk density; %HR, loss on drying; dc, tapped density; %H, hygroscopicity; Ie, inter-particle porosity; %Pf, particle size; IC, Carr's index; Iθ, homogeneity index; ICd, cohesion index; DE, effervescence test; IH, Hausner ratio; DCD, disintegration time with disk; Α, angle of repose; DSD, disintegration time without disk; t , flow ability.*

experimental determination or calculations of various parameters are converted to "r" values by applying specific factors, representing radii of the diagram. The diagram is formed by connecting radius values with linear segment [13], having 0 as a minimum value, 10 as maximum value, and 5 as minimum acceptable value as shown in **Figure 1**. The resultant diagram indicates suitability of the material to be compressed by direct compression.

#### **3.3 Calculation of various indices**

Optimum mechanical strength, disintegration behavior, and rheological characteristics of powder are estimated on the basis of the following indices [11, 14] calculated using "r" values of the basic parameters.

#### *3.3.1 Parametric index*

Parametric index is the ratio of number of parameters having "r" values equal to or greater than 5 to the total number of parameters determined during the study. Parametric index was calculated using the following equation:

$$\text{I.P} = \frac{\text{No.P} \ge 5}{\text{No.Pt}} \tag{8}$$

where I.P. is the parametric index, No. P ≥ 5 is the number of parameters with "r" values equal to or more than 5, and No. Pt is the total number of parameters determined.

Acceptability limit corresponds to a score of 5.

#### *3.3.2 Parameter profile index*

Parameter profile index is the average of "r" values of all the parameters determined in the study, and its acceptable limit corresponds to a score of 5.

IPP = Average of "r" value of all parameters

### *3.3.3 Good compressibility and bucco-dispersibility index*

Good compressibility and bucco-dispersibility index (IGCB) is the product of parameter profile index and reliability factor:

$$\mathbf{I.G.C.B} = \mathbf{I.P.P.x}f\tag{9}$$

problems are encountered when the ratio of the fine particles exceeds 25% of the

**Fraction Average diameter of**

*DOI: http://dx.doi.org/10.5772/intechopen.92444*

*Particle size distribution for the determination of homogeneity index.*

**particles of fraction**

0.355–0.500 Fm + 2 427 dm + 2 271 0.212–0.355 Fm + 1 283 dm + 1 127 0.100–0.212 Fm 156 dm 0 0.050–0.100 Fm 1 75 dm 1 81 <0.050 Fm 2 25 dm 2 131

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical…*

Size distribution of the particles provided a basis for assigning limit values to homogeneity index. **Table 3** indicates the size of the sieve (in mm), average particle size in each fraction, the difference in average particle size in the fraction between

**Corresponding diameter (dm … dm n)**

**Difference of dm with major fraction**

As the sieve range 0.100–0.212 mm falls in the middle of other factions, it corresponds to major fraction. A proportion of 60% in major fraction (Fm) is considered to be the minimum acceptable value, that is, 5. Distribution of particles into other fractions is considered to be Gaussian. Limit of homogeneity index is 0–0.02.

Initially, relative humidity was calculated based on the establishment of three intervals because the percentage relation obtained from the measurement of the humidity of the substance does not follow a linear relation with respect to the correct behavior of the dust. Humidity below 1% makes the powder too dry, and electrostatic charge is induced, which affects the rheology. Furthermore, low humidity percentages do not allow compression of the substance (moisture is necessary for compacting powders). Moreover, more than 3% moisture causes caking, in addition to favoring the adhesion to punches and dyes. Consequently, it was considered that this parameter should present optimal experimental values from 1 to 3%. Nevertheless, experience using the SeDeM diagram has demonstrated no significant variations in the results, so the previous three intervals of relative humidity can be simplified to the calculation of the parameter; thus, finally, the

The SeDeM/SeDeM-ODT expert system is based on the experimental study and quantitative determination of the characterization parameters of powdered substances, with the aim to determine suitability for producing tablets by direct compression technology. Additionally, this expert system also provides formulations with a minimum number of excipients and reduces the lead time during formulation development [11]. Some of the reported applications of SeDeM-ODT expert

Direct compression is the most preferred technique for tablet manufacturing due to simplicity, material safety, and cost-effectiveness. Direct compression technique cannot be applied for every formulation because of some strict requirements

formulation.

**Table 3.**

**Sieve size (mm)**

0.100 and 0.212, and others.

linear criterion of treatment of results is adopted.

system are summarized below:

**177**

**4. Practical applications of SeDeM-ODT expert system**

**4.1 Formulation development by direct compression technology**

where *f* is the reliability factor.

Inclusion of more parameters in the study will increase reliability factor. Its values are as follows:


#### **3.4 Determination of acceptable limit values for each parameter of SeDeM-ODT expert system**

Certain limit values are set for each parameter included in SeDeM-ODT expert system on the basis of experimental results and values described in the *Handbook of Pharmaceutical Excipients* [24]. The rationale for establishing limit values for each parameter is given below.

Limit values of bulk density, tapped density, inter-particle porosity, and Carr's index are calculated from the extreme values of these parameters given in the *Handbook of Pharmaceutical Excipients* and official monograph.

Limit of Icd is obtained by compressing powder into tablet under maximum compression force to get tablets without capping. Maximum hardness at which tablets are compressed without any capping is taken as upper limit, while 0 is taken as lower limit. 0 shows that powder cannot be compressed into tablet.

Limits for angle of repose, IH, and powder flow were set as per official monograph. **Table 2** shows correlation of flow characteristics of powder to various rheological parameters on the basis of the USP [20].

Limits for hygroscopicity are based upon the *Handbook of Pharmaceutical Excipients* [24]. As per published literature [25–27], rheological and compression


#### **Table 2.**

*Relationship between flow characteristics and various rheological parameters.*

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical… DOI: http://dx.doi.org/10.5772/intechopen.92444*


**Table 3.**

*3.3.3 Good compressibility and bucco-dispersibility index*

parameter profile index and reliability factor:

where *f* is the reliability factor.

• For 15 parameters, *f* = 0.971

• For 12 parameters, *f* = 0.952

• For 08 parameters, *f* = 0.900

**SeDeM-ODT expert system**

parameter is given below.

**Table 2.**

**176**

values are as follows:

*Advanced Functional Materials*

Good compressibility and bucco-dispersibility index (IGCB) is the product of

Inclusion of more parameters in the study will increase reliability factor. Its

• For infinite number of parameters, *f* = 1 (maximum value)

**3.4 Determination of acceptable limit values for each parameter of**

Certain limit values are set for each parameter included in SeDeM-ODT expert system on the basis of experimental results and values described in the *Handbook of Pharmaceutical Excipients* [24]. The rationale for establishing limit values for each

Limit values of bulk density, tapped density, inter-particle porosity, and Carr's

Limit of Icd is obtained by compressing powder into tablet under maximum compression force to get tablets without capping. Maximum hardness at which tablets are compressed without any capping is taken as upper limit, while 0 is taken

Limits for angle of repose, IH, and powder flow were set as per official monograph. **Table 2** shows correlation of flow characteristics of powder to various

Limits for hygroscopicity are based upon the *Handbook of Pharmaceutical Excip-*

**Flow characteristics 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 >1.6 >66

index are calculated from the extreme values of these parameters given in the

*Handbook of Pharmaceutical Excipients* and official monograph.

rheological parameters on the basis of the USP [20].

*Relationship between flow characteristics and various rheological parameters.*

as lower limit. 0 shows that powder cannot be compressed into tablet.

*ients* [24]. As per published literature [25–27], rheological and compression

I*:*G*:*C*:*B ¼ I*:*P*:*P x *f* (9)

*Particle size distribution for the determination of homogeneity index.*

problems are encountered when the ratio of the fine particles exceeds 25% of the formulation.

Size distribution of the particles provided a basis for assigning limit values to homogeneity index. **Table 3** indicates the size of the sieve (in mm), average particle size in each fraction, the difference in average particle size in the fraction between 0.100 and 0.212, and others.

As the sieve range 0.100–0.212 mm falls in the middle of other factions, it corresponds to major fraction. A proportion of 60% in major fraction (Fm) is considered to be the minimum acceptable value, that is, 5. Distribution of particles into other fractions is considered to be Gaussian. Limit of homogeneity index is 0–0.02.

Initially, relative humidity was calculated based on the establishment of three intervals because the percentage relation obtained from the measurement of the humidity of the substance does not follow a linear relation with respect to the correct behavior of the dust. Humidity below 1% makes the powder too dry, and electrostatic charge is induced, which affects the rheology. Furthermore, low humidity percentages do not allow compression of the substance (moisture is necessary for compacting powders). Moreover, more than 3% moisture causes caking, in addition to favoring the adhesion to punches and dyes. Consequently, it was considered that this parameter should present optimal experimental values from 1 to 3%. Nevertheless, experience using the SeDeM diagram has demonstrated no significant variations in the results, so the previous three intervals of relative humidity can be simplified to the calculation of the parameter; thus, finally, the linear criterion of treatment of results is adopted.

## **4. Practical applications of SeDeM-ODT expert system**

The SeDeM/SeDeM-ODT expert system is based on the experimental study and quantitative determination of the characterization parameters of powdered substances, with the aim to determine suitability for producing tablets by direct compression technology. Additionally, this expert system also provides formulations with a minimum number of excipients and reduces the lead time during formulation development [11]. Some of the reported applications of SeDeM-ODT expert system are summarized below:

#### **4.1 Formulation development by direct compression technology**

Direct compression is the most preferred technique for tablet manufacturing due to simplicity, material safety, and cost-effectiveness. Direct compression technique cannot be applied for every formulation because of some strict requirements in terms rheological characteristics and compressibility [2, 3]. Intensive experimentation is carried out to get a final powder blend suitable for direct compression. SeDeM-ODT expert system has been applied for characterization of powder to predict its suitability for direct compression. The main advantage of the expert system is to avoid extra experimentation during formulation development, reducing time and cost of formulation development [11]. Various mathematical equations are used for powder characterization, and a data base is developed which facilitates the selection of excipients having desired characteristics, at pre-formulation level.

microcrystalline cellulose). The model drug, domperidone, was characterized, according to the established procedure, and was found deficient in dimension, compressibility, and flowability/powder flow factors. Index of good compressibility (IGC) value of domperidone was below the acceptable limit. Combination of diluents was used to get a diluent system (**Figure 3**) capable of compensating lower IGC value of domperidone. The developed formulations resulted in tablets fulfilling the official requirements without any stability issue with minimum experimental work. In a study SeDeM expert system was applied for establishing a design space and determination of critical quality attributes during formulation development of cap-

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical…*

Cefuroxime axetil and paracetamol have poor rheological characteristics and compressibility. Inderbir and Pradeep [30] applied the SeDeM expert system for formulation of these two APIs by direct compression. Both the APIs were characterized following standard procedure, and excipients were selected on the basis of

**4.2 Determination of the amount of excipient required for the compression of**

Josep et al. developed a mathematical Equation [14] for the calculation of the amount of diluent required for the preparation of tablets by direct compression containing glucosamine salt (750 mg). Glucosamine is used in high dose (750 mg/ tablet) and presents poor rheological characteristics and compressibility. Six direct compression diluents were characterized according to the SeDeM expert system, and mathematical equation was applied for the calculation of the amount of excipient to compensate the deficiencies. The theoretical model was validated by study-

*CP* <sup>¼</sup> <sup>100</sup> � *RE* � *<sup>R</sup>*

*RE* � *RP* � <sup>100</sup><sup>Þ</sup> (10)

topril SR matrix by direct compression [29].

*DOI: http://dx.doi.org/10.5772/intechopen.92444*

ing the calculated amounts experimentally.

*SeDeM diagram of microcrystalline cellulose and Tablettose-80 [28].*

mathematical calculations [14].

**an API**

**Figure 3.**

**179**

Johny et al. applied SeDeM expert system in formulation development of orodispersible tablets of ibuprofen by direct compression [11]. They developed formulation after characterization of API (ibuprofen) and 21 disintegrants. Various parameters were determined for all the 21 disintegrants, according to the standard protocols, converted to "r" values by applying specific factors, and presented as SeDeM diagram (**Figure 2**). Deficiencies were found out for each disintegrant and were solved by proper selection of other excipients.

In another study SeDeM expert system was applied for formulation development of effervescent tablets of domperidone by direct compression [28]. During the study SeDeM profile was developed for domperidone, effervescent pair (citric acid, tartaric acid, and sodium bicarbonate), and two diluents (Tablettose-80 and

**Figure 2.** *SeDeM diagram of various disintegrants [11].*

#### *SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical… DOI: http://dx.doi.org/10.5772/intechopen.92444*

microcrystalline cellulose). The model drug, domperidone, was characterized, according to the established procedure, and was found deficient in dimension, compressibility, and flowability/powder flow factors. Index of good compressibility (IGC) value of domperidone was below the acceptable limit. Combination of diluents was used to get a diluent system (**Figure 3**) capable of compensating lower IGC value of domperidone. The developed formulations resulted in tablets fulfilling the official requirements without any stability issue with minimum experimental work.

In a study SeDeM expert system was applied for establishing a design space and determination of critical quality attributes during formulation development of captopril SR matrix by direct compression [29].

Cefuroxime axetil and paracetamol have poor rheological characteristics and compressibility. Inderbir and Pradeep [30] applied the SeDeM expert system for formulation of these two APIs by direct compression. Both the APIs were characterized following standard procedure, and excipients were selected on the basis of mathematical calculations [14].

### **4.2 Determination of the amount of excipient required for the compression of an API**

Josep et al. developed a mathematical Equation [14] for the calculation of the amount of diluent required for the preparation of tablets by direct compression containing glucosamine salt (750 mg). Glucosamine is used in high dose (750 mg/ tablet) and presents poor rheological characteristics and compressibility. Six direct compression diluents were characterized according to the SeDeM expert system, and mathematical equation was applied for the calculation of the amount of excipient to compensate the deficiencies. The theoretical model was validated by studying the calculated amounts experimentally.

$$CP = 100 - \left(\frac{RE - R}{RE - RP}\right) \times 100\,\text{(}\tag{10}$$

**Figure 3.** *SeDeM diagram of microcrystalline cellulose and Tablettose-80 [28].*

in terms rheological characteristics and compressibility [2, 3]. Intensive experimentation is carried out to get a final powder blend suitable for direct compression. SeDeM-ODT expert system has been applied for characterization of powder to predict its suitability for direct compression. The main advantage of the expert system is to avoid extra experimentation during formulation development, reducing time and cost of formulation development [11]. Various mathematical equations are used for powder characterization, and a data base is developed which facilitates the selection of excipients having desired characteristics, at pre-formulation level. Johny et al. applied SeDeM expert system in formulation development of orodispersible tablets of ibuprofen by direct compression [11]. They developed formulation after characterization of API (ibuprofen) and 21 disintegrants. Various parameters were determined for all the 21 disintegrants, according to the standard protocols, converted to "r" values by applying specific factors, and presented as SeDeM diagram (**Figure 2**). Deficiencies were found out for each disintegrant and

In another study SeDeM expert system was applied for formulation development of effervescent tablets of domperidone by direct compression [28]. During the study SeDeM profile was developed for domperidone, effervescent pair (citric acid, tartaric acid, and sodium bicarbonate), and two diluents (Tablettose-80 and

were solved by proper selection of other excipients.

*Advanced Functional Materials*

**Figure 2.**

**178**

*SeDeM diagram of various disintegrants [11].*

#### **Figure 4.**

*Strategy proposed by SeDeM expert system to develop orally disintegrating tables [14].*

where CP is the % of corrective excipient, RE is the mean-incidence radius value (compressibility) of the corrective excipient, R is the mean-incidence radius value to be obtained in the blend, RP is the mean-incidence radius value (compressibility) of the API to be corrected, and R is the 5 as 5 is the minimum value that is regarded as necessary in order to achieve good compression [14].

blend containing ribavirin and other ingredients included in granule formulation. Powder blend was compacted under varying degree of experimental conditions, and selected in the optimal conditions with better granule characteristics. He claimed that it decreased experimental work and resulted in granules suitable for

*SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical…*

*SeDeM-ODT diagram for Itopride HCl before and after taste masking [33].*

**4.4 Prediction of behavior of a new pharmaceutical ingredient (APIs and**

SeDeM-ODT expert system has been applied for the determination of suitability of new powdered substances for direct compression. The powder substance may be a new API or excipients which are intended to be used in formulation of compact

Sune-Negre et al. used the SeDeM method to characterize an active product ingredient in powder form (API SX-325) and to determine whether it is suitable for direct compression [12], applying the profile to the SeDeM diagram. Twelve parameters were determined for the powdered raw material according to the standard protocols, presented as SeDeM diagram, indicating suitability of the material for direct compression. Findings of the study implied deficient rheological characteristics and poor stability. The product was declared hygroscopic on the basis of SeDeM profile and tended to capture moisture, worsening rheological characteristics and impairing its stability. Various precautionary measures were suggested for prevention of negative effects like drying of the material and tablet preparation in

an environment of controlled humidity (relative humidity below 25%).

ents was developed, as shown in **Figure 6**.

Sune-Negre et al. applied SeDeM expert system for characterization of 51 directly compressible excipients [12]. On the basis of the results, directly compressible excipients were classified into different groups with different rheological and compressibility capability, and a periodic table of directly compressible excipi-

good compressibility of 8.832 [12]. SeDeM expert system has been applied for the

They showed that the best excipient for direct compression should have an index of

compression and encapsulation.

*DOI: http://dx.doi.org/10.5772/intechopen.92444*

**excipients)**

**Figure 5.**

solid dosage forms.

**181**

**Figure 4** presents a strategy for the development of orally disintegrating tablets by direct compression by applying the proposed equation (Eq. (10)).

### **4.3 Elucidation of the effect of processing on characteristics of powder substances**

SeDeM-ODT expert system has been applied for elucidation of the effect of processing parameters on characteristics of powder substance. Amjad et al. applied SeDeM-ODT expert system for predicting the effect of taste masking on the rheological characteristics, mechanical strength, and disintegration behavior of highly water-soluble drug (Itopride HCl) [31]. Itopride HCl is a bitter-tasting, highly water-soluble drug with poor rheological characteristics. Taste of Itopride HCl was masked by water-based wet granulation technique using HPMC as taste masking polymer. Itopride HCl powder was the subjected characterization as per SeDeM-ODT expert system, before and after taste masking, and results were compared (**Figure 5**) to evaluate the effect on rheological characteristics, disintegration behavior, and mechanical strength. Dimension factor and flowability/powder flow factors were below the acceptable limit. Comparison of results before and after taste masking showed that taste masking significantly improved the mechanical strength and rheological characteristics and decreased the disintegration behavior of powder. It was concluded that in order to formulate by direct compression, the formulation will require large amount of disintegrant to overcome increase in mechanical strength after taste masking.

Amjad [32] has applied SeDeM-ODT expert system for the optimization of process variables of roller compaction. He studied ribavirin powder and powder *SeDeM-ODT Expert System: A Solution to Challenges in Characterization of Pharmaceutical… DOI: http://dx.doi.org/10.5772/intechopen.92444*

**Figure 5.** *SeDeM-ODT diagram for Itopride HCl before and after taste masking [33].*

blend containing ribavirin and other ingredients included in granule formulation. Powder blend was compacted under varying degree of experimental conditions, and selected in the optimal conditions with better granule characteristics. He claimed that it decreased experimental work and resulted in granules suitable for compression and encapsulation.
