8.1. Preparation of Solid SNEDDS (S-SNEDDS)shodhganga.inflibnet.ac.in/bitstream/10603/32498/14/14_chapter 8.pdf · study the effect of variable on the selected responses. Every excipient

Result and Discussion

Dept of Pharmaceutics, JSSCP, Mysore 168

8.1. Preparation of Solid SNEDDS (S-SNEDDS)

The acceptability of prepared liquid SNEDDS was enhanced by solidification

of the liquid SNEDDS into S-SNEDDS by adsorption method. An advantage of the

adsorption technique is uniformity of content and high drug loading is possible

compared to other techniques67. The S-SNEDDS offers better stability on long storage

and advantages of a solid dosage form (e.g. low production cost, convenience of

process control, high stability, reproducibility and better patient compliance).

The ideal solid matrix excipients for preparation of S-SNEDDS should have

high adsorption capacity, which could hold a larger liquid SNEDDS163 and facilitate

the preparation of tablets28. Thus the adsorbents used in the study, to load SNEDDS,

are Aerosil 200, Porous polystyrene beads (PPB) and Accurel MP 1000, which have

high surface area, can hold high amount of liquid on it. Adsorption efficiency of any

carrier is dependent on its porosity, surface area and hydrogen bonding capacity160.

All powders were dry and free flowing. The lipid formulation would be

retained either partially or completely within intraparticular pores of the adsorbent.

Further, addition of SNEDDS, resulted in a sudden formation of paste or single

agglomerate, which may corresponds to a pendular state in stepwise growing

behavior103.

The Porous carriers are characterized by stable uniform porous structures, high

surface areas, tunable pore sizes with narrow distributions, and well-defined surface

properties, thus allowing them to adsorb and release the drugs in a more reproducible

and predicable manner164.



Aerosil 200 has the mean particle size of 12nm and specific surface area

(BET) of 380 ± 30 m2/g. Because of its high specific surface area and oil adsorbing

capacity, loading efficiency of SNEDDS was higher than PPB and Accurel (Table

8.1). The PPB are inert, stable over a wide pH range and to extreme conditions of

temperature and humidity. PPB essentially consists of hydrocarbon backbone with

benzene rings and are devoid of any functional groups and has particle size of 0.3-

1µm. The loading efficiency of SNEDDS was relatively less in PPB than aerosil 200.

The porous structures in the Accurel act like tiny sponges which absorb the

liquid through capillary forces and keep them inside. It has particle size of 0.2 µm

which provide large surface area for adsorption. The loading efficiency was higher

than PPB, but lesser than aerosil 200. By considering the high loading capacity and

better flow property, The SNEDDS loaded with adsorbent were selected for

preparation of tablets103.

Table 8.1: Flow rate and Loading efficiency of SNEDDS loaded in different

adsorbents

SNEDDS Adsorbent Angle of repose*

°

Loading efficiency*

%

Efavirenz

Aerosil 18.7±0.15 138.15±2.89

PPB 23.2±0.25 112.64±1.76

Accurel 22.6±0.17 120.86±2.1

Atorvastatin Calcium

Aerosil 19±0.37 132.74±2.28

PPB 23.7±0.29 118.31±2.79

Accurel 22±0.19 126.59±1.21

Rosuvastatin Calcium

Aerosil 19.1±0.12 135.43±1.56

PPB 23.5±0.26 121.62±2.37

Accurel 22.3±0.18 124.47±1.82

* Mean±Standard deviation, n=3



Scanning electron microscopy (SEM)

The scanning electron micrographs of Accurel, Porous polystyrene beads,

Aerosil and SNEDDS loaded with the adsorbents are shown in Figure 8.1- 8.3.

The surface topography of accurel clearly shows highly porous structure with

pores of almost similar size arranged as a network. The morphology of SNEDDS

loaded with accurel (Figure 8.1) showed relatively rough surface, suggesting that drug

might be attached and dispersed onto the surface of the solid carrier at either

molecular level or as precipitates165. The Accurel microporous structures on surface

and in the matrix will form channels for water to infiltrate, which could eases the

microemulsion formation and dispersion.

Figure 8.1: Scanning electron micrographs of Accurel (A, B) and Accurel loaded

SNEDDS (C, D)



Figure 8.2: Scanning electron micrographs of Porous polystyrene beads (A, B)

and Porous polystyrene beads loaded SNEDDS (C, D)

The Scanning electron micrographs of the SNEDDS loaded with PPB showed

the separate, uniform and spherical particles with small pits on surfaces (Figure 8.2).

Upon SNEDDS loading, these pits filled up, accommodating SNEDDS within the

micropores.



Figure 8.3: Scanning electron micrographs of Aerosil 200 (A) and Aerosil 200

loaded SNEDDS (B, C and D)

The SEM photographs of Aerosil 200 and S-SNEDDS are shown in Figure

8.3. Aerosil 200 (Figure 8.3, A) appeared as fine particles with rough-surface.

However, The SNEDDS loaded with aerosil (Figure 8.3 B, C and D) appeared as

rough surfaces granular particles, indicating that the liquid SNEDDS was absorbed or

coated on aerosil. No distinct crystals were seen on the surface of the particles.126

Such molecular dispersion of the drug on the solid carrier may account for the

enhanced drug release158.

Differential Scanning Calorimetry

The DSC thermogram showed pronounced endothermic peak at 137.5°C for

efavirenz, that corresponding to its melting point. Accurel loaded SNEDDS showed

the peak at 162.2°C, that corresponding to the melting point of Accurel. The peak at



82.05°C in PPB loaded SNEDDS, which corresponds to the melting point of PPB.

The DSC thermogram of aerosil loaded SNEDDS did not show the peak at the entire

temperature range. The absence of drug peak in SNEDDS loaded adsorbents was due

to presence of drug in molecularly dissolved state in the lipid excipients. The DSC

thermograms of efavirenz and efavirenz SNEDDS loaded in adsorbents are shown in

the Figure 8.4.

Figure 8.4: Differential scanning calorimetric thermogram: (A) Efavirenz (B)

Accurel loaded Efavirenz SNEDDS (C) PPB loaded Efavirenz SNEDDS (D)

Aerosil loaded Efavirenz SNEDDS.


atorvastatin calcium, that corresponding to its melting point. The SNEDDS loaded in

Accurel, PPB and Aerosil, did not show peak at the entire temperature range. The

absence of drug peak in SNEDDS loaded adsorbents was due to presence of drug in

molecularly dissolved state in the lipid excipients. The DSC thermograms of

atorvastatin calcium and atorvastatin calcium SNEDDS loaded with adsorbents are

shown in the Figure 8.5.



Figure 8.5: Differential scanning calorimetric thermogram: (A) Atorvastatin

calcium (B) Accurel loaded Atorvastatin calcium SNEDDS (C) PPB loaded

Atorvastatin calcium SNEDDS (D) Aerosil loaded Atorvastatin calcium

SNEDDS.


rosuvastatin calcium, that corresponding to its melting point. The SNEDDS loaded in

Accurel, PPB and Aerosil, did not show peak at the entire temperature range. The

absence of drug peak in SNEDDS loaded adsorbents was due to presence of drug in

molecularly dissolved state in the lipid excipients. The DSC thermograms of

rosuvastatin calcium and rosuvastatin calcium SNEDDS loaded with adsorbents are

shown in the Figure 8.6.



Figure 8.6: Differential scanning calorimetric thermogram: (A) Rosuvastatin

calcium (B) Accurel loaded Rosuvastatin calcium SNEDDS (C) PPB loaded

Rosuvastatin calcium SNEDDS (D) Aerosil loaded Rosuvastatin calcium

SNEDDS.

X-ray diffraction studies (XRD)

Efavirenz

X-ray diffractogram showed multiple peaks for efavirenz, indicating

crystalline nature of drug (Figure 8.7 (A)). However, X-ray diffractogram of

SNEDDS (B) showed diffused spectra without any characteristic peaks of efavirenz.

The crystalline peaks of efavirenz were absent in S-SNEDDS indicating that the drug

was not in crystalline form. The results correlate with the DSC studies.



Figure 8.7: X-ray diffraction patterns of Efavirenz (A) and S-SNEDDS (B)

Atorvastatin calcium

X-ray diffractogram showed multiple peaks for Atorvastatin calcium,

indicating crystalline nature of drug (Figure 8.8 (A)). However, X-ray diffractogram

of SNEDDS (B) showed diffused spectra without any characteristic peaks of

Atorvastatin calcium. The crystalline peaks of Atorvastatin calcium were absent in

S-SNEDDS indicating that the drug was not in crystalline form. The results correlate

with the DSC studies.



Figure 8.8: X-ray diffraction patterns of Atorvastatin calcium (A) and

S-SNEDDS (B)

Rosuvastatin calcium

X-ray diffractogram showed multiple peaks for rosuvastatin calcium,

indicating crystalline nature of drug (Figure 8.9 (A)). However, X-ray diffractogram

of SNEDDS (B) showed diffused spectra without any characteristic peaks of

rosuvastatin calcium.

The crystalline peaks of rosuvastatin calcium were absent in S-SNEDDS

indicating that the drug was not in crystalline form. The results correlate with the

DSC studies.



Figure 8.9: X-ray diffraction patterns of Rosuvastatin calcium (A) and

S-SNEDDS (B)



8.2. EFAVIRENZ

8.2.1. Preparation of Efavirenz loaded SNEDDS tablet

The tablets were prepared by direct compression technique, direct

compression (DC) is most effective, fastest and simplest method in the manufacturing

of tablet. The method also secures the drug from moisture and heat. Furthermore, the

tablet characteristics such as stability, dissolution, and bioavailability of the active

drugs were reported to be improved using the DC method166. In the process of

compaction, the material is metamorphose from loose powder form into a solid

compact. The composition of granules/powders and the parameters of the

compression process determine the strength of tablets167.

Micro crystalline cellulose (MCC), poly vinyl pyrollidone (PVP) and sodium

starch glycolate (SSG) were used as directly compressible diluent, binder and super

disintegrating agent.

The microcrystalline cellulose PH 101 (MCC) is an excellent filler/flow-aid

for direct compression with an average particle size of 50µm that attributes to the

excellent batch flowability and compressibility properties168. Due to its high surface

area and enormous internal porosity it is capable to absorb and retain a large quantity

of liquid and also absorbs the any squeezing of lipid occurs while punching of

tablets169.

PVP K 30 is used as binder because of its directly compressible property.

Sodium starch glycolate (SSG) is added in the formulations as it belongs to category

of directly compressible super disintegrants which swell upto 5-10 times in less than

30s. The inclusion of disintegrants improved the general redispersion of all the

formulations28.



Analysing the effect of multiple excipients in various ratio by trial and error

or changing one separate factor at a time (COST) ways are usually ineffective, as the

output obtained through these trials do not accredit the recognition of interaction

effects with the formulation ingredients170.

Design of experiments (DOE) is a scientific approach applied to understand

the processes in a larger way and to resolve how the inputs influence the

response(s)171, 172. In the current research work, 23 factorial design was applied to

study the effect of variable on the selected responses.

Every excipient is included to suit the needs of product use and processibility.

The major types of adjuvants used are diluents, binders, disintegranting agents and

lubricants which are nearly present in all tablet preparations173, 174.

By conducting a group of preliminary trials by varying the relative ratio of the

selected three components i.e. MCC, PVP, SSG and on the previous related

experiences, the upper and the lower limits of each variable were defined (Table 8.2).

If all of the possible combination for the excipients in the initial formulation system is

to be evaluated, a full factorial DOE could requires 8 studies, as shown in Table 8.3



Table 8.2: Variables in 23 factorial designs

Independent variable Levels

Low(mg) High(mg)

A: MCC 200.00 300.00

B: PVP 12.00 20.00

C: SSG 8.00 16.00

Dependent variable

Y1 Hardness (kg)

Y2 Disintegration Time (sec)

Y3 % Cumulative drug release (%)

Table 8.3: Matrix of 23 factorial designs for Efavirenz loaded SNEDDS tablet

Run

Factor 1 Factor 2 Factor 3

A:MCC

mg

B:PVP

mg

C:SSG

mg

1 300 12 8

2 300 20 16

3 200 12 8

4 200 12 16

5 200 20 16

6 300 20 8

7 200 20 8

8 300 12 16



Table 8.3 reports the corresponding 8 runs of experimental design in which the

mixture component compositions are indicated. The test mixtures were prepared

according to this experimental design and analysed for their physical characteristics.

It was observed that adding lactose into MCC, improved the compactibility.

Efavirenz SNEDDS tablets, showed faster release of drug due to water soluble lactose

used as solid matrixing agent.

8.2.2. Micromeritic properties of powder blend

The results of bulk density, tapped density, angle of repose, Carrs index and

Hausners ratio are given in the Table 8.4. The angle of repose, Carrs index and

Hauseners ratio confirms the good flow property.

Table 8.4: Micromeritic properties

Run Bulk

Density

(g/cc) *

Tapped

Density

(g/cc) *

Angle of

repose*

°

Carrs index

%*

Hausners

ratio*

1 0.310±0.001 0.422±0.002 29.06±0.531 26.54±0.494 1.361±0.004

2 0.327±0.001 0.437±0.003 27.11±0.478 25.17±0.592 1.336±0.002

3 0.324±0.002 0.435±0.003 28.45±0.287 25.51±0.448 1.342±0.002

4 0.319±0.002 0.429±0.001 28.72±0.421 25.64±0.293 1.344±0.005

5 0.321±0.003 0.432±0.002 28.94±0.610 25.69±0.503 1.345±0.005

6 0.322±0.001 0.434±0.002 29.13±0.477 25.8±0.391 1.347±0.003

7 0.317±0.002 0.430±0.001 28.93±0.639 26.27±0.491 1.356±0.001

8 0.311±0.001 0.428±0.002 29.21±0.224 27.33±0.5 1.377±0.002




8.2.3. Experimental design.

Table 8.5: Observed Response in 23 Factorial Design for Efavirenz loaded

SNEDDS tablet

Std

Run

Factor

1

Factor

2

Factor

3

Response

1

Response

2

Response

3

A:MCC

mg

B:PVP

mg

C:SSG

mg

Hardness

kg

Disintegration

Time (Sec)

%

Cumulative

drug release

2 1 300 12 8 5.9 125 76.4

8 2 300 20 16 4.6 98 87.3

1 3 200 12 8 5.2 112 82.6

5 4 200 12 16 3.4 72 99.2

7 5 200 20 16 4.3 92 90.6

4 6 300 20 8 7.1 152 68.5

3 7 200 20 8 6.3 138 71.2

6 8 300 12 16 4 85 95.4

The result depicts (Table 8.5) that variables chosen have strong influence on

the selected responses, as hardness, disintegration time and percentage cumulative

drug release values were in the range of 3.4-7.1 kg, 72-152s and 68.5-99.2%

respectively.

The application of factorial design yielded the following regression equations.

Hardness = +4.775+6.0E-003 * MCC+0.118 * PVP-0.256* SSG

Disintegration Time= +105.0+0.115* MCC+2.68 * PVP-5.62 * SSG

% Cumulative drug release = +84.22-0.04 * MCC-1.12 * PVP+2.30 * SSG



Where negative values indicate a negative effect of a specific variable on the

response factors and positive values indicate a positive effect of a specific variable on

the response factors. The polynomial regression results were expressed using 3-D graphs

and contour plots (Figure 8.10-8.11)

Hardness

Low concentration of PVP has positive effect on the hardness of the tablet the

hardness was between 3.4-5.9kg (Table 8.5). With increase in concentration of PVP,

the hardness was increased upto 7.1 kg. MCC and SSG have slight effect on the

hardness.The increase in hardness of tablet with increase in concentration of MCC in

some formulations is attributed to large free hydroxyl groups and hence the interaction

forces (hydrogen bonding) in a contact point might be stronger175.

Disintegration Time (DT)

SSG has negative effect on the disintegration time, with increase in the

concentration of SSG in tablets, the disintegration time was decreased. At the low

concentration, the disintegration time was between 112-152 sec, as the concentration

of SSG increased,the disintegration time decreased to 72-98 sec. The decrease in DT

with increase in the concentration of SSG was due to its rapid swelling property.

In certain runs (1 and 6), MCC increased the DT as it may indirectly increase

the hardness of the tablet. MCC accelerates water penetration into tablets, due to

wicking action, that can cause enormous swelling of SSG, and this revealed the

superdisintegrant property of SSG136.



Percentage Cumulative drug release

The extent of drug release, however, is dependent on the reversible attraction

and surface adsorption of efavirenz and the oily formulation onto the adsorbents.

Therefore, physical properties of the ingredients used to prepare the solid compacts

have a profound effect on the emulsion release rate. This relationship between the

formulation ingredients (independent variables) and emulsion release rates (dependent

variables) was elucidated using 3D graphs (Figure 8.10).

Figure 8.10: Three-dimensional response surface plot depicting the impact of

MCC:PVP, MCC:SSG and SSG:PVP on hardness, disintegration time and %

drug release respectively



Figure 8.11: Counter Plot Showing impact of MCC:PVP, MCC:SSG and

SSG:PVP on hardness, disintegration time and % drug release respectively

There is no significant contribution by eliminated terms from the equation on

the prediction of Cumulative percentage drug release. Results of regression analysis

showed coefficients of MCC and PVP bearing a negative sign, i.e., with increase in

the concentration of these factors show negative effect on percentage cumulative drug

release. This is due to, with increase in the concentration of MCC and PVP, the

hardness of tablet increase which leads to delay in tablet disintegration and thus

hindered the drug release. Whereas SSG showed positive effect, with increase in the

concentration of SSG, the DT significantly decrease which attributes the faster release

of drug.



The Response surface plots and contour plots exhibits, as the concentration of

PVP increases, the hardness of the tablets increases due to the increased bonding

between the particles.

8.2.4. Evaluation of tablets

Slight deviation associated with the tablet weight could be due to variation in

the bulk density of the formulations. Tablet thickness was in the range of 3.00-3.2mm

and was constant for all the formulations. Percentage weight variation and thickness

suggested that there is low probability of any variability corrolated with the tablet

machine or the method of preparation of tablets.

Friability of all the prepared tablets shows in the range of 0.61-0.92%, which

is well within the limit i.e >1% that confirms the good mechanical resistance. Drug

content was 98-102% which complied to the pharmacopeial limits (Table 8.6).

Table 8.6: Evaluation of Efavirenz tablets

Run Thickness

(mm) *

Friability*

%

% Weight

variation*

Drug

content

(%)*

1 3.2±0.070 0.81±0.021 0.149±0.004 99.12±1.41

2 3.1±0.141 0.73±0.035 0.049±0.006 98.43±2.82

3 3.2±0.141 0.89±0.028 0.249±0.003 101.07±0.70

4 3.1±0.070 0.92±0.141 0.049±0.004 98.62±1.21

5 3.0±0.212 0.74±0.036 0.149±0.002 102.17±1.62

6 3.2±0.070 0.61±0.042 0.049±0.005 100.28±0.86

7 3.1±0.070 0.68±0.031 0.149±0.006 102.15±1.21

8 3.2±0.212 0.78±0.025 0.049±0.003 99.37±0.92




From the experimental results (Table 8.5), the effects of all studied variables

and the variable interactions were graphically and statistically interpreted for all

responses. The results of ANOVA indicated that all models were significant (p <

0.05) for all response parameters investigated. Model simplification was carried out

by eliminating non-significant terms (p > 0.05) in polynomial equations. Values of

"Prob > F" less than 0.0500 in all the cases indicates model terms are significant. The

Pred R-Squared is in reasonable agreement with the Adj R-Squared. The signal to

noise ratio is measured by Adeq Precision and ratio greater than 4 is desirable. The

value shows much higher than 4 confirms an adequate signal (Table 8.7).

Table 8.7: Summary of results of regression analysis for responses

Value F-value p-value

Hardness

R-Square 0.9865

97.16

0.0003 Adj R-Squared 0.9763

Pred R-Squared 0.9458

Adeq Precision 26.291

Disintegration Time

R-Square 0.9867

99.08

0.0003 Adj R-Squared 0.9768



% Cumulative Drug Release

R-Square 0.9950

266.61

< 0.0001 Adj R-Squared 0.9913





8.2.5. Optimisation

To obtain the optimized tablet, the required limits of the response values were

clearly defined (hardness of 4, disintegration time of less than 80 sec and percentage

cumulative drug release of more than 95%) (Table 8.8). The combinations of

variables which resulted in tablets meeting the required specifications were calculated

using the design expert software. The overlapping of the obtained result over the

predicted values confirms the practicability and validation of the model.

Table 8.8: Optimisation of final efavirenz tablet

Value MCC

(mg)

PVP

(mg)

SSG

(mg)

Hardness

(kg)

Disintegration

Time(sec)

% Cumulative

drug release (%)

Predicted 278.75 12 15.88 4 79.9 96.1

Actual 278.75 12 15.88 4 78 97

Relative

error (%) 0 2.37 0.9

8.2.6. Reconstitution properties of optimized S-SNEDDS tablets

The globule size and polydispersity index of the solid and liquid SNEDDS are

presented in Table 8.9. The globule size of both systems was less than 150 nm. The

droplet size of the nanoemulsion formed from the S-SNEDDS was slightly increased,

but the difference is not statistically significant compared to the liquid SNEDDS. The

SNEDDS loaded tablet emulsifies fast and robust to dilution.



Table 8.9: Globule size with polydispersity index of the reconstituted

nanoemulsions

Formulation Globule size (nm) Polydispersity index (PDI)

Liquid SNEDDS 142.8 0.581

Solid SNEDDS 145 0.725

Figure 8.12: Globule size distribution

8.2.7. Comparative in vitro drug release studies and Release kinetics

The comparative dissolution profiles of optimized Efavirenz SNEDDS loaded

tablet formulation and marketed preparation (Sustiva) was carried out in 0.1M HCl.

The dissolution profile shows that the optimized Efavirenz SNEDDS loaded tablet

exhibited faster drug release (97.6% at 40 min) whereas market preparation showed

22.27% at 40 min (Figure 8.13). Thus the optimized Efavirenz SNEDDS loaded tablet

showed a 4-5 fold increase in dissolution rate. Diffusion, swelling and erosion are the

most important drug release mechanisms. The drug release from the Efavirenz

SNEDDS loaded tablet tends to follow nearly zero-order kinetics (R2=0.9821)

followed by non-Fickian kinetics (n value 0.74), owing to interplay of diffusion and

convection mechanisms.



Figure 8.13: In-vitro drug release profiles of Efavirenz SNEDDS tablets and

market formulation

8.2.8. Pharmacokinetics studies

The chromatograms of rat plasma spiked with Efavirenz and after oral

administration of S-SNEDDS are shown in Figure 8.14-8.15.

Figure 8.14: Typical chromatogram of rat plasma spiked with Efavirenz

0

20

40

60

80

100

120

0 10 20 30 40 50

SNEDDS Tablet

Marketed formulation

% C

umul

ativ

edr

ug r

elea

se

Time (min)



Figure 8.15: Representative chromatogram of plasma sample after oral

administration of efavirenz SNEDDS tablets to rats

Pharmacokinetic parameters

The pharmacokinetic parameters of efavirenz absorption are summarized in

Table 8.10. The Figure 8.16 depicts the mean plasma concentration profile as a

function of time obtained by the pharmacokinetic studies carried out in rats for

SNEDDS tablets and pure drug. The plasma level profiles were significantly

increased for SNEDDS tablets compared to pure drug.

Table 8.10: Pharmacokinetic parameters

Product Cmax

(mcg/ml) *

Tmax

(h) *

Kel

(h-1) *

T1/2

(h) *

(AUC)0t

(mcg/ml×h)*

Efavirenz 10.46±2.27 3.7±0.62 0.1776±0.02 3.9±0.28 95.39±6.23

Efavirenz SNEDDS tablets

42.6±3.79 1.1±0.37 0.2038±0.05 3.4±0.16 388.49±12.7




The results showed that Cmax of SNEDDS tablets was 4.1 times higher than

that of pure drug. Additionally, Tmax of the SNEDDS tablets was all shorter than

that of the pure drug, suggesting that self emulsifying technique could improve drug

release and absorption in GIT. It indicated that the absorption of efavirenz was

evidently improved after it was dispersed in solid SNEDDS formulations. There were

no significant differences between the half-life and elimination rate constant of

efavirenz and SNEDDS tablets.

Many factors could be involved in the improvement of efavirenz

bioavailability. Due to relatively high lipophilicity, efavirenz could have a good

permeability through epithelia cells of gastrointestinal (GI) tract. However, the poor

aqueous solubility efavirenz limited its dissolution and resulted in a low

bioavailability. After oral administration of SNEDDS tablets, the emulsion readily

dispersed, and no dissolution of efavirenz was required since the drug was dissolved

in the oil phase of the emulsion. In addition, Labrafac PG, a medium chain

triglyceride, could induce the activation of the “ideal brake mechanism” which slowed

down GI transit time; moreover, it was reported that medium chain triglyceride like

Labrafac PG had an enhanced effect on the intestinal cells to allow the lipid particles

through the cell layer 27.



Figure 8.16: Plasma drug level profiles of optimized SNEDDS tablets and pure

drug.



8.3. Atorvastatin calcium (AC)

8.3.1. Preparation of Atorvastatin calcium loaded SNEDDS tablet

In the present study, the design of experiment (23 factorial design) was

employed to systematically evaluate the effect of varying the amount of MCC, PVP

and SSG on the hardness, disintegration time, percentage cumulative drug release.

Every excipient is included to suit the needs of product use and processibility. The

major types of adjuvants used are diluents, binders, disintegranting agents and

lubricants which are nearly present in all tablet preparations176 .

The microcrystalline cellulose PH 101 (MCC) which is an excellent

filler/flow-aid for direct compression. PVP K 30 is used because of its directly

compressible property that acts as binder. Sodium starch glycolate (SSG) are added in

the formulations as it belongs to directly compressible super disintegrants which swell

upto 5-10 times in less than 30s.



experiences, the upper and the lower limits for each variable were defined

(Table 8.11).



Table 8.11: Variables in 23 factorial design


Low(mg) High(mg)

A: MCC 250 350

B: PVP 8.75 15.75

C: SSG 5 14

Dependent variable

Y1 Hardness (kg)



Table 8.12: Matrix of 23 Factorial Design for AC loaded SNEDDS tablet

Std

Run


A:MCC

mg

B:PVP

mg

C:SSG

mg

1 1 250 8.75 5

4 2 350 15.75 5

6 3 350 8.75 14

2 4 350 8.75 5

8 5 350 15.75 14

7 6 250 15.75 14

5 7 250 8.75 14

3 8 250 15.75 5



Table 8.12 reports the corresponding 8 runs of experimental design in which

the mixture component compositions are indicated. The test mixtures were prepared

according to this experimental design and analysed for their physical characteristics.

It was observed that adding lactose into MCC, improved the compactibility.

AC SNEDDS tablets, showed faster release of drug due to water soluble lactose used

as solid matrixing agent.


The results of bulk density, tapped density, angle of repose, carrs index and


Hausners ratio indicates that powder blends have good flow property.


Run Bulk

Density

(g/cc) *

Tapped

Density

(g/cc) *

Angle of

repose*

°

Carrs

index

%*

Hausners

ratio*

1 0.335±0.002 0.463±0.003 24.32±0.01 27.6±0.21 1.382±0.003

2 0.380±0.003 0.512±0.003 23.14±0.03 25.78±0.09 1.347±0.005

3 0.374±0.006 0.505±0.005 23.26±0.02 25.94±0.18 1.350±0.002

4 0.379±0.008 0.510±0.006 23.02±0.01 25.68±0.16 1.345±0.004

5 0.382±0.004 0.516±0.005 23.78±0.03 25.97±0.2 1.350±0.006

6 0.343±0.006 0.473±0.003 24.13±0.02 27.48±0.08 1.379±0.004

7 0.339±0.004 0.471±0.004 24.95±0.03 28.02±0.19 1.389±0.004

8 0.347±0.002 0.477±0.003 24.19±0.01 27.25±0.15 1.374±0.005





The summary of result data obtained of various responses is presented in Table

8.14.

Table 8.14: Observed Response in 23 Factorial Design for AC loaded

SNEDDS tablet

Std

Run

Factor

1

Factor

2

Factor

3

Response

1

Response

2

Response

3

A:MCC

mg

B:PVP

mg

C:SSG

mg

Hardness

Kg

Disintegration

time Sec

% cumulative

drug release

1 1 250.00 8.75 5.00 3.8 99 97.5

4 2 350.00 15.75 5.00 7.1 184 76.4

6 3 350.00 8.75 14.00 5.2 117 96.8

2 4 350.00 8.75 5.00 4.9 121 92.1

8 5 350.00 15.75 14.00 6.8 176 79.8

7 6 250.00 15.75 14.00 6.4 144 87.9

5 7 250.00 8.75 14.00 4.1 91 99.1

3 8 250.00 15.75 5.00 5.9 154 83.4

The results depicits (Table 8.14) that variables chosen have strong influence

on the selected responses, as hardness, disintegration time and percentage cumulative

drug release values were in the range of 3.8-7.1 kg, 91-184s and 76.4-99.1%

respectively.




Hardness =-1.12361+9.50000E-003 * MCC+0.29286 * PVP+0.022222* SSG

Disintegration time =-39.45833+0.27500 * MCC+8.21429 * PVP-0.83333 * SSG

% Cumulative drug release =+127.85278-0.057000 * MCC-2.07143* PVP+

0.39444 * SSG


response factor and positive value indicates positive effect of a specific variable. The

polynomial regression results were expressed using 3-D graphs and contour plots (Figure

8.17-8.18)

The ANOVA studies indicated that all models were significant (p < 0.05) for

all response parameters scrutinized. Model simplification was done by removing non-

significant terms (p > 0.05) in polynomial equations.

Hardness

The regression equation depcits that PVP has a strong effect on the hardness

of the tablet. As the concentration of PVP increased there is significant increase in the

hardness of tablet. MCC and SSG has slight effect on the hardness. The increase in

hardness with increase in concentration of MCC in few formulations observed,

attributed to large free hydroxyl groups which makes the interaction forces (hydrogen

bond) in a contact point might be stronger.

Disintegration time

SSG has negative effect on the disintegration time of the tablets. With increase

in the concentration of SSG, disintegration time decreases, due to its rapid swelling

property. At the low concentration, the disintegration time was between 97-184 sec,



as the concentration of SSG increased,the disintegration time decreased to 91-176 sec.

The decrease in DT with increase in the concentration of SSG was due to its rapid

swelling property.

In certain runs (2 and 5), MCC increased the DT as it may indirectly increase

the hardness of the tablet. MCC accelerates water penetration into tablets, due to

wicking action, that can cause enormous swelling of SSG, and this revealed

superdisintegrant property of SSG136.

Percentage cumulative drug release

The Response surface plots and contour plots exhibits, as the concentration of

SSG increased, the percentage cumulative drug release increased from 76.4-99.1%.

The SSG makes the tablet to disintegrate and exposes them to large dissolution

medium leading to greater release. There is no significant contribution by eliminated

terms from the equation on the prediction of Cumulative percentage drug release.

Microcrystalline cellulose being insoluble has negative influence on the

dissolution when used at very high concentration. However this did not warrant

attention, as the drug release was in some cases it acts as disintegrant which ensured

faster and complete dissolution rate176, 177.

MCC and PVP have negative effect on the cumulative drug release. This may

be due to contribution of these factors in increase in the hardness178. The Response

surface plots and contour plots exhibits, as the concentration of SSG increases,.



Figure 8.17: Three-dimensional response surface plot depicting the impact of MCC:PVP, MCC:SSG and MCC:SSG on hardness, disitegration time and %

drug release respectively.


SSG:PVP on hardness, disintegration time and % drug release respectively




Tablet weight showed very low variability as was expected from the excellent

flow of the direct compression excipients used. The thickness of the prepared tablet

also show low variability related to the good flow and consistency of compression

force. The friability value was found to be less than 1% that confirms the good

mechanical resistance of the tablets. Drug content was 97-102% which complied with

pharmacopeial limits. The result of thickness, friability, % weight variation and drug

content are given in the Table 8.15.

Table 8.15: Evaluation of AC tablets

Run Thickness

(mm) *

Friability*

%

% Weight

variation*

Drug content

(%)*

1 3.16±0.057 0.73±0.03 0.075±0.002 97.33±0.577

2 3.06±0.057 0.65±0.04 0.322±0.007 98.66±1.154

3 3.1±0.1 0.82±0.02 0.123±0.003 102±1.011

4 3.13±0.057 0.76±0.03 0.275±0.002 101.66±0.577

5 3.3±0.057 0.67±0.03 0.322±0.004 100.66±1.527

6 3.2±0.173 0.78±0.02 0.075±0.002 101±1.73

7 3.26±0.057 0.74±0.02 0.275±0.003 99.66±2.08

8 3.1±0.173 0.63±0.03 0.075±0.004 98.33±0.577


From the experimental results, the effects of all studied variables and the

variable interactions were graphically and statistically interpreted for all responses.

The results of ANOVA indicated that all models were significant (p < 0.05) for all

response parameters investigated. Model simplification was carried out by eliminating



non-significant terms (p > 0.05) in polynomial equations. Values of "Prob > F" less

than 0.0500 in all the cases indicates model terms are significant. The Pred R-Squared

is in reasonable agreement with the Adj R-Squared. The signal to noise ratio is

measured by Adeq Precision and ratio greater than 4 is desirable. The value shows

much higher than 4 confirms an adequate signal (Table 8.16). This model can be used

to navigate the design space.

The high values of r2 shown by the polynomial relationships assure high

statistical validityof polynomial models for fitting to the experimental data. The

linearity of the correlation plots between predicted and observed responses confirms

high prognostic ability of the postulated model.



Hardness

R-Square 0.9786

60.98

0.0009 Adj R-Squared

Pred R-Squared

Adeq Precision

0.9626 0.9144 19.081

Disintegration Time

R-Square 0.9958

323.04

< 0.0001

Adj R-Squared 0.9928




R-Square 0.9810

68.99

0.0007

Adj R-Squared 0.9668





8.3.5. Optimisation


clearly defined (hardness of 4.5kg, disintegration time of 100 sec and % cumulative

release of more than 98%) (Table 8.17). The combinations of variables which resulted

in tablets meeting the required specifications were calculated using the design expert

software. The overlapping of the obtained result over the predicted values confirms

the practicability and validation of the model.

Table 8.17: Optimisation of final AC tablet

Value MCC

(mg)

PVP

(mg)

SSG

(mg)

Hardness

(Kg)

Disintegration

Time(sec)

% Cumulative

drug release(%)

Predicted 250.02 10.08 13.37 4.5 100 98.00

Actual 250.02 10.08 13.37 4.5 98 97.5

Relative

error 0 2.0 0.51


The z-average diameter and polydispersity index of the solid and liquid

SNEDDS are presented in Table 8.18. As shown in the table, the z-average droplet

sizes of both systems were less than 50 nm. The droplet size of the nanoemulsion

from the solid SNEDDS was slightly increased, but the difference is not statistically

significant. S-SNEDDS formulation disperse quickly and completely when subjected

to aqueous environment under mild agitation and showed robustness to high dilutions.



Table 8.18: Globule size with polydispersity index of the reconstituted

nanoemulsions

Formulation z-Average diameter (nm) Polydispersity index (PDI)


Solid SNEDDS 49.4 0.262



The comparative dissolution profiles of optimized AC SNEDDS loaded tablet

and market preparation (Astin) was carried out in 0.1M HCl. The dissolution profile

showed that the optimized AC SNEDDS loaded tablet exhibited faster drug release

(97.5% at 40 min) whereas marketed preparation shows 32.7% at 40 min. Thus the

optimized AC SNEDDS loaded tablet showed almost 3 fold increase in dissolution

rate. Diffusion, swelling and erosion are the most important drug release mechanisms.

The drug release from the AC SNEDDS loaded tablet tends to follow nearly zero-

order kinetics followed by non-Fickian kinetics, owing to interplay of diffusion and

convection mechanisms.



Figure 8.20: In-vitro drug release profiles of AC SNEDDS tablets and market

formulation

8.3.8. Pharmacokinetics studies12

The Pharmacokinetic study shows that the OPT AC SNEDDS tablets showed

significant improvement of Cmax and AUC of the drug while compared to its pure

form. The chromatograms of rat plasma spiked with AC and after oral administration

of SNEDDS tablets are shown in Figure 8.21-8.22.

Figure 8.21: Typical chromatogram of rat plasma spiked with AC

0

20

40

60

80

100

120

0 10 20 30 40 50

AC SNEDDS Tablets

Market Formulation

Time(min)

% C

umul

ativ

edr

ug r

elea

se



Figure 8.22: Representative chromatogram of plasma sample after oral

administration of AC SNEDDS tablets to rats


Product Cmax

(mcg/ml) *

Tmax

(h) *

Kel

(h-1) *

T1/2

(h) *

(AUC)0t

(mcg/ml×hr) *

AC 6.92±1.76 2.5±0.25 0.031±0.002 22.35±1.22 73.56±8.52

AC SNEDDS tablets

48.02±5.98 1.2±0.18 0.035±0.033 19.8±1.73 386.2±15.69


The results showed that Cmax of AC SNEDDS tablets were 6.93 times higher

than that of pure drug. Additionally, Tmax of the AC SNEDDS tablets was all shorter

than that of the pure drug, suggesting that self emulsifying technique could improve

drug release and absorption in GIT. It indicated that the absorption of AC was

evidently improved after it was dispersed in solid SNEDDS formulations (Figure

8.23).



The increase in Cmax and AUC is because, after oral administration of AC

SNEDDS tablets, the emulsion readily dispersed, and no dissolution of atorvastatin

calcium was required since the drug was in the dissolved form in the oil phase of the

emulsion. In addition, Capmul, a medium chain triglyceride and surfactants could

improve the permeation of drug. There were no significant differences between the

half-life and elimination rate constant of AC and AC SNEDDS tablets.


drug.

0

10

20

30

40

50

60

0 4 8 12 16 20 24

Plas

ma

drug

conc

entr

atio

n (m

cg/m

l)

Time(h)

Pure drug

SNEDDS tablets



8.4. Rosuvastatin calcium (RC)

8.4.1. Preparation of RC loaded SNEDDS tablet

The tablets were prepared by direct compression technique, direct

compression (DC) is most effective, fastest and simplest method in the manufacturing

of tablet. The method also secures the drug from moisture and heat.

Micro crystalline cellulose (MCC), poly vinyl pyrollidone (PVP) and sodium

starch glycolate (SSG) were used as directly compressible diluent, binder and super

disintegrating agent.

The microcrystalline cellulose PH 101 (MCC) is an excellent filler/flow-aid

for direct compression with an average particle size of 50µm that attributes to the

excellent batch flowability and compressibility properties173. Due to its high surface

area and enormous internal porosity it is capable to absorb and retain a large quantity

of liquid and also absorbs the any squeezing of lipid occurs while punching of

tablets169.

PVP K 30 is used as binder because of its directly compressible property.

Sodium starch glycolate (SSG) is added in the formulations as it belongs to category

of directly compressible super disintegrants which swell upto 5-10 times in less than

30s. The inclusion of disintegrants improved the general redispersion of all the

formulations28.

Every excipient is included to suit the needs of product use and processibility.

To identify the most important factors among all the factors screening is done at

beginning of the experimental procedure.





experiences, the upper and the lower limits of each variable were defined (Table

8.20). If all of the possible combination for the excipients in the initial formulation

system is to be evaluated, a full factorial DOE could requires 8 studies, as shown in

Table 8.20

Table 8.20: Variables in 23 factorial design


Low(mg) High(mg)

A: MCC 250 350

B: PVP 8.75 15.75

C: SSG 5 14

Dependent variable

Y1 Hardness (kg)



Table 8.21: 23 Factorial Design for RC loaded SNEDDS tablet

Std

Run


A:MCC

mg

B:PVP

mg

C:SSG

mg

1 1 250 8.75 5

4 2 350 15.75 5

6 3 350 8.75 14

2 4 350 8.75 5

8 5 350 15.75 14

7 6 250 15.75 14

5 7 250 8.75 14

3 8 250 15.75 5




The results of bulk density, tapped density, angle of repose, Carrs index and


Hausners ratio confirms the good flow property.


Run Bulk

Density

(g/cc) *

True

Density

(g/cc) *

Angle of

repose*

°

Carrs index

(%)*

Hausners

ratio*

1 0.339±0.001 0.467±0.003 24.73±0.04 27.41±0.18 1.377±0.04

2 0.382±0.003 0.518±0.002 24.26±0.04 26.25±0.11 1.356±0.002

3 0.371±0.002 0.502±0.003 24.37±0.02 26.09±0.06 1.352±0.005

4 0.385±0.002 0.511±0.004 23.94±0.03 24.65±0.21 1.327±0.004

5 0.389±0.004 0.521±0.002 24.11±0.04 25.33±0.15 1.339±0.003

6 0.340±0.002 0.478±0.003 25.62±0.02 28.84±0.19 1.405±0.003

7 0.344±0.002 0.473±0.004 25.93±0.02 27.27±0.12 1.375±0.002

8 0.352±0.003 0.482±0.004 24.91±0.03 26.97±0.09 1.369±0.005



In the present study, the design of experiment methodology was employed to

systematically evaluate the effect of varying the amount of MCC, PVP and SSG on

the Hardness, Disintegration time, percentage cumulative drug release. The summary

of result data obtained of various responses is presented in Table 8.23.



Table 8.23: Observed Response in 23 Factorial Design for RC loaded SNEDDS

tablet

Std

Run

Factor

1

Factor

2

Factor

3

Response

1

Response

2

Response

3

A:MCC

mg

B:PVP

mg

C:SSG

mg

Hardness

Kg

Disintegration

time Sec

% cumulative

drug release

1 1 250 8.75 5 3.4 105 97.9

4 2 350 15.75 5 7.5 192 76

6 3 350 8.75 14 5.4 123 97.6

2 4 350 8.75 5 5.1 130 92.7

8 5 350 15.75 14 7.1 169 82.1

7 6 250 15.75 14 6.2 139 88.5

5 7 250 8.75 14 3.9 88 99.3

3 8 250 15.75 5 6 160 81.6

The result depicts (Table 8.23) that variables chosen have strong influence on

the selected responses, as hardness, disintegration time and percentage cumulative

drug release values were in the range of 3.4-7.1kg, 88-192s and 76-99.3%

respectively.

The hardness of the tablets were in the range of 3.4-7.5kg. The disintegration

time of the prepared tablets were in the range of 88-192 sec. The drug release at the

end of 40 min was between 76-99.3%.


Hardness =-2.72083+0.014000 * MCC+0.32143 * PVP+0.016667 * SSG



Disintegration time =-28.93056+0.30500 * MCC+7.64286 * PVP-1.88889 *

SSG

% Cumulative drug release = +124.48819-0.047250 * MCC-2.11786 * PVP +

0.53611* SSG


response factors and positive values indicate a positive effect of a specific variable on

the response factors. The polynomial regression results were expressed using 3-D graphs

and contour plots (Figure 8.24-8.25). The contour plots depict the concentration of the

factors at which the particular response produced.

Hardness

PVP has a significant effect on the hardness of the tablet whereas MCC and

SSG have a slight effect. Hence the concentration of PVP was the main factor

affecting the hardness. The PVP has a positive effect on the hardness of the tablet, at

low concentration the hardness was between 3.4-5.4 kg. With increase in

concentration of PVP, the hardness of the tablet increased to 7.5kg (Table 8.23). The

increase in hardness with increase in concentration of MCC, attributed to large free

hydroxyl groups which make the interaction forces (hydrogen bond) in a contact point

might be stronger.

Disintegration time

As it can be seen from the plot (Figure 8.25), concentration of SSG has

significant effect on the disintegration time. The model equation relating

Disintegration time showed SSG has negative effect on the DT. MCC and PVP

showed positive effect, with increase in the concentration of MCC and PVP, the DT



increased due to the contribution of these factors in increase in hardness. SSG has

negative effect on the disintegration time.

Low concentration of SSG showed the disintegration time of 105-192 sec. As

the concentration was increased, the disintegration time decreased to 88 sec. The

formulation containing the higher concentration of SSG, shows faster disintegration

followed by higher dissolution rate. As soon as the glycolate comes in contact with

water, it rapidly absorbs which causes enormous swelling that leads to the rapid

disintegration. There is no significant contribution by eliminated terms from the

equation on the prediction of disintegration time.179

Percentage cumulative drug release

Results of regression analysis showed coefficients of MCC and PVP bearing a

negative sign, i.e., with increase in the concentration of these factors show negative

effect on percentage cumulative drug release. This is due to, with increase in the

concentration of MCC and PVP, the hardness of tablet increase which leads to delay

in tablet disintegration and thus hindered the drug release. The SSG has positive effect

on percentage cumulative drug release, due to the swelling property of SSG which

increase the disintegration. The drug release at the end of 40 min was between in the

range of 76-99.3%.



Figure 8.24: Three-dimensional response surface plot depicting the impact of

MCC:PVP, PVP:SSG and SSG: PVP on hardness, disitegration time and %

cumulative drug release respectively


SSG:PVP on hardness, disintegration time and percentage drug release

respectively




Tablet thickness was in the range of 3.1-3.26 mm and was considered constant

for all the formulations (Table 8.24). Percentage weight variation and thickness

suggested that there is a low possibility of any variability associated with the tablet

press or the method of preparation of tablets. Friability of less than 1% in all the

prepared formulations confirms mechanical strength of the tablets. Drug content was

in the range of 98.7-101.2%, which complied with pharmacopeial limits.

Table 8.24: Evaluation of RC tablets

Run Thickness

(mm) *

Friability*

%

% Weight

variation*

Drug content

(%)*

1 3.16±0.057 0.65±0.02 0.254±0.004 99.1±0.909

2 3.06±0.057 0.77±0.02 0.453±0.003 98.9±1.262

3 3.1±0.1 0.86±0.03 0.143±0.004 99.6±1.614

4 3.13±0.057 0.59±0.05 0.055±0.005 100.6±0.98

5 3.3±0.057 0.63±0.04 0.254±0.003 98.7±1.861

6 3.2±0.173 0.71±0.03 0.342±0.002 101.2±1.334

7 3.26±0.057 0.82±0.03 0.541±0.004 99.8±1.758

8 3.1±0.173 0.66±0.02 0.254±0.002 100.3±0.891


From the experimental results, the effects of all studied variables and the

variable interactions were graphically and statistically interpreted for all responses.

The results of ANOVA indicated that all models were significant (p < 0.05) for all

response parameters investigated. Model simplification was carried out by eliminating

non-significant terms (p > 0.05) in polynomial equations. Values of "Prob > F" less



than 0.0500 in all the cases indicates model terms are significant. The Pred R-Squared

is in reasonable agreement with the Adj R-Squared.

The signal to noise ratio is measured by Adeq Precision and ratio greater than

4 is desirable. The value shows much higher than 4 confirms an adequate signal

(Table 8.25). This model can be used to navigate the design space.

The high values of r2 shown by the polynomial relationships assure high

statistical validityof polynomial models for fitting to the experimental data. The

linearity of the correlation plots between predicted and observed responses confirms

high prognostic ability of the postulated model.



Hardness

R-Square 0.9788

61.60 0.0008 Adj R-Squared 0.9629



Disintegration Time

R-Square 0.9907

142.27 0.0002 Adj R-Squared 0.9838




R-Square 0.9777

58.56 0.0009 Adj R-Squared 0.9610





8.4.5. Optimisation


clearly defined (hardness of 4.5, disintegration time of less than 103 sec and

percentage cumulative drug release of more than 98%) (Table 8.26). The

combinations of variables which resulted in tablets meeting the required specifications

were calculated using the design expert software. The overlapping of the obtained

result over the predicted values confirms the practicability and validation of the

model.

Table 8.26: Optimisation of RC final tablet

Value MCC PVP SSG Hardness (Kg)

Disintegration Time (sec)

% Cumulative drug release (%)

Predicted 267.73 10.08 14 4.5 103 98.00

Actual 267.73 10.08 14 4.5 106 97.1

Realtive

error(%)

2.91 0.91


The z-average diameter and polydispersity index of the solid and liquid

SNEDDS are presented in Table 8.27. As shown in the table, the z-average droplet

sizes of both systems were less than 41nm. The droplet size of the nanoemulsion from

the S-SNEDDS was slightly increased, but is not statistically significant. SNEDDS

emulsifies as soon as it comes in contact with the dissolution media and also it is

robust to higher dilutions.



Table 8.27: Droplet size with polydispersity index of the reconstituted

nanoemulsions

Formulation z-Average diameter (nm) Polydispersity index (PDI)


Solid SNEDDS 40.1 0.194



The comparative dissolution profiles of optimized RC SNEDDS loaded tablet

formulation and market preparation (Rosavel10mg) was carried out in 0.1M HCl. The

dissolution profile showed that the optimized RC SNEDDS loaded tablet exhibited

faster drug release (97.1% at 40 min) whereas market preparation shows 36.9% at 40

min. Thus the optimized RC SNEDDS loaded tablet showed almost 3 fold increase in

dissolution rate. Diffusion, swelling and erosion are the most important drug release

mechanisms. The drug release from the RC SNEDDS loaded tablet tends to follow

nearly zero-order kinetics followed by non-Fickian kinetics, owing to interplay of

diffusion and convection mechanisms



Figure 8.27: In-vitro drug release profiles of RC SNEDDS tablets and market

formulation

8.4.8. Pharmacokinetics studies13

The Pharmacokinetic study shows that the optimised RC SNEDDS tablets

shows significant improvement of Cmax and bioavailability of the drug compared to

the pure drug. The chromatograms of rat plasma spiked with RC and after oral

administration of SNEDDS tablets are shown in Figure 8.28-8.29.

Figure 8.28.: Typical chromatogram of rat plasma spiked with RC

0

20

40

60

80

100

120

0 10 20 30 40 50

% C

umul

ativ

e dr

ug re

leas

e

Time (min)

RC SNEDDS Tablets

Market Formulation



Figure 8.29. Representative chromatogram of plasma sample after oral

administration of RC SNEDDS tablets to rats

The pharmacokinetic parameters of RC absorption are summarized in Table

8.28. The Figure 8.30 depicts the mean plasma concentration profile as a function of

time obtained by the pharmacokinetic studies carried out in rats for SNEDDS tablets

and pure drug. The plasma level profiles were significantly increased for SNEDDS

tablets compared to pure drug.


Product Cmax

(mcg/ml) *

Tmax

(h) *

Kel

(h-1) *

T1/2

(h) *

(AUC)0t

(mcg/ml×hr) *

RC 7.92±1.81 5±0.79 0.042±0.005 16.4±1.83 52.9±6.89

RC S-SNEDDS 57.4±3.05 1.9±0.24 0.048±0.002 14.2±1.21 418.6±14.95


The results showed that Cmax of SNEDDS tablets was 7.24 times higher than

that of pure drug. Additionally, Tmax of the SNEDDS tablets was all shorter than

that of the pure drug, suggesting that self emulsifying technique could improve drug



release and absorption in GIT. It indicated that the absorption of RC was evidently

improved after it was dispersed in solid SNEDDS formulations. There were no

significant differences between the half-life and elimination rate constant of RC and

SNEDDS tablets.


drug.

9. Stability testing

The results of the stability study (Table 8.29) of prepared formulations stored

at 40°C and 75% relative humidity for 6 month with accordance with ICH

guidelines139. The drug content and dissolution behaviour of prepared formulations

remain unchanged during storage. FT-IR studies confirm the no interaction of drug

and excipient occurs during the storage.

0

10

20

30

40

50

60

0 4 8 12 16 20 24

Plas

ma

drug

con

cent

ratio

n (m

cg/m

l)

Time(Hrs)

Pure drug

SNEDDS tablets



Table 8.29: Stability study data of optimized formulations

Sample name: Efavirenz Loaded SNEDDS tablets

Storage condition: 40°C /75% RH

Testing interval FT-IR Study Drug content

(%)

% cumulative

drug release

Initial Complies 98.72±0.47 97.89±0.89

1 month Complies 97.67±0.29 96.72±0.74

2 month Complies 96.28±0.6 96.02±0.28

3 month Complies 95.45±0.19 95.18±0.13

6 month Complies 95.02±0.22 95.01±0.30

Sample name: AC Loaded SNEDDS tablets



1 month Complies 98.34±0.64 98.22±0.62

2 month Complies 98.02±0.28 97.68±0.86

3 month Complies 97.28±0.46 97.10±0.37

6 month Complies 96.33±0.19 96.45±0.29

Sample name: RC Loaded SNEDDS tablets



1 month Complies 98.43±0.83 97.98±0.85

2 month Complies 98.09±0.26 97.24±0.47

3 month Complies 97.67±0.28 96.62±0.64

6 month Complies 97.14±0.17 96.15±0.57


8.1. Preparation of Solid SNEDDS (S-SNEDDS)shodhganga.inflibnet.ac.in/bitstream/10603/32498/14/14_chapter 8.pdf · study the effect of variable on the selected responses. Every excipient

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