The Purpose Of Stability Testing Biology Essay

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Stability is defined as the extent to which a product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics (i.e. chemical, physical, microbiological and biopharmaceutical), that it possessed at the time of its manufacture.

The purpose of stability testing is to gather evidence on the variation in quality of drug substance or drug product with time under the influence of a number of environmental factors, such as temperature, humidity and light, and to assign a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions.

In the past, elaborate and time consuming procedures to test a drug or drug product for stability were followed. These tests were conducted for a time period corresponding to the actual normal storage time in stock or in use. The application of general chemical kinetic principles to stability testing of drugs and drug products allowed prediction of rate constants and shelf lives in relatively short time studies, carried out at elevated temperatures. It became easier to identify the most stable and most suitable formulation in a comparatively shorter period of study. According to rule-of-thumb methods, the rate of reaction is said to double for each 10ï‚°C rise in temperature (Guidance for Industry QIA (R2) Stability Testing Of New Drug Substances and Products, 2003).

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The International Conference on Harmonization (ICH) has proposed guidelines towards stability testing of new drug substances and drug products for a registration application within the three areas of the EC, Japan and the USA. It lacks advice for stability testing of products for use in the more extreme climatic conditions found in many other developing countries. The WHO Expert Committee guidelines on specifications for pharmaceutical preparations cover these countries and do not distinguish between established and new drug substances and drug products. However, the ICH guidelines are more widely followed than any other guideline for stability testing of drug substances and drug products.

The ICH guidelines provides a general indication on the requirements for stability testing leaving sufficient flexibility to encompass a variety of different practical situations required for specific scientific situations and characteristics of the materials being evaluated.

According to the ICH guidelines, accelerated testing for 6 months should be carried out at a temperature at least 15C above the designated long term testing storage temperature combined with the appropriate relative humidity conditions for that temperature. Long term testing should be done for a minimum period of 12 months. For instance, if a product needs a long term storage under refrigerated condition, accelerated testing should be conducted at 25±2C/60±5% RH. The designated long term testing conditions will be reflected in the labeling and expiration date. For products that require storage at 25±2C/60±5% RH, an accelerated testing at 40±2C/75±5% RH for 6 months must be conducted. Where "significant change" occurs during 6 months storage under conditions of accelerated stability testing at 40±2C/75±5% RH, an additional testing at an intermediate condition such as 30±2C/65±5% RH should be conducted for a 12 month period (Stability testing of active substances and pharmaceutical products, 2006).

The CDER guideline Guidance Q1A (R2), 2003 specifies Stability Testing of New Drug Substances and Products. According to these guidelines, for new drug products intended to be stored in a refrigerator; long term testing should be at a storage condition of 5±3C for a minimum period of 12 months and the accelerated testing should be at 25±2C/60±5% RH for 6 months.

"Significant change" at an accelerated condition is defined as:

A 5% loss in potency from the initial assay value of a batch of drug substance or drug product.

Any specified degradant exceeding its specification limit.

The product exceeding its pH limits.

Dissolution exceeding the specification limits for 12 capsules or tablets.

Failure to meet specifications for appearance and physical properties, e.g. color, phase separation, re-suspendability, delivery per actuation, caking, hardness etc.

"Significant change" at "accelerated condition" is defined as failure to meet the specifications. The long term testing should be continued for a sufficient time beyond 12 months to cover the shelf life at appropriate test periods. Testing frequency should be sufficient to establish the stability characteristics of the drug substance or drug product. Testing under the defined long term conditions will normally be every 3 months over the first year, every 6 months over the second year, and then annually.

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Out of the five lipids namely TM, TP, TS, GB and GP, MTX-SLNs of TP and TS gave stable batches in terms of particle size in the preliminary short term stability studies. Therefore, these batches were selected for long-term stability studies.

In the present work, two batches TP-S17 and TS-S17 were subjected to the following storage conditions as recommended in the ICH guidelines:

Refrigeration as control (5±3C) for 12 months

25±2C/60±5% RH for 12 months

30±2C/65±5% RH for 6 months

40±2C/75±5% RH for 6 months

7.2 EXPERIMENTAL

7.2.1 Preparation of stability batches

Stability batches of each of the two selected formulations viz. TP-S17 and TS-S17 were prepared. 600ml of each batch as per composition in Section 5.3….. was prepared for stability testing. Both the batches were prepared using hot homogenization technique on the lab scale APV 2000 high pressure homogenizer.

Quantities were calculated for 600ml of each batch. All the ingredients were weighed separately. The respective lipid was taken separately in a beaker and melted and the drug dispersed into the lipid melt. Surfactants B and C were added to the hot melt and heated till clear. Solubilizers D, E, F and G were added to the lipid melt and heated till a clear drug-lipid melt was obtained. In a separate beaker, requisite quantity of water was heated to 80°C and the surfactants L and M were dispersed into the aqueous phase and stirred using magnetic stirrer till a clear solution was obtained. The hot lipid melt was added under constant stirring to the hot aqueous phase. This pre-emulsion was stirred on Ultra Turrax T25 at 24,000 rpm for 5 mins, maintaining the temperature at 80°C. The hot pre-emulsion was homogenized on a pre-heated APV 2000 homogenizer. The pressure was gradually increased from 100 bars to 1200 bars and homogenization carried out for 10 cycles. The obtained lipid nanoparticles were instantly cooled into an ice bath to generate solid lipid nanoparticles. The obtained MTX-SLNs were filled in Type I amber colored glass vials and sealed with rubber closures and aluminum seals.

7.2.2 Conduction of stability studies

The MTX-SLN samples were stored at the following stability conditions as per ICH guidelines: Refrigeration, 25ï‚°C/60% RH, 30ï‚°C/65% RH and 40ï‚°C/75% RH. Samples were withdrawn at periodic intervals of 1, 2, 3, 6 months for all the conditions and additional 9 and 12 months for refrigeration and 25ï‚°C/60% RH. Analysis was conducted on all the samples subsequently.

7.2.3 Evaluation of stability samples

All the MTX-SLN samples were characterized for the following parameters prior and after stability testing:

7.2.3.1 Physicochemical evaluation

Physicochemical evaluation was noted by visual observation of the samples for color and appearance. Results are tabulated in Tables 7.1 and 7.2.

7.2.3.2 pH

pH is another physicochemical attribute which is an important parameter in stability testing. pH was measured on a calibrated, standardized digital pH meter. Results are tabulated in Tables 7.3 and 7.4. Figures 7.1-7.4 represent the comparative pH values of the MTX-SLNs of TP and TS at the four stability conditions respectively and Figures 7.5 and 7.6 are graphical representation of pH values at the four stability conditions over the period of time tested in TP-S17 MTX-SLNs and TS-S17 MTX-SLNs respectively.

7.2.3.3 Particle size distribution

Particle size distribution is the most important parameter for assessing the stability of the prepared solid lipid nanoparticles. The particle size distribution was measured on the N5 Beckman Particle Size Analyzer for both the unimodal and SDP functions.

The data was evaluated statistically by applying one way ANOVA with post Dunnett's t-test by comparing control against the stability conditions over the period of time tested.

Results are tabulated in Tables 7.5 and 7.6. Figure 7.7 represents the comparative SDP mean particle size analysis of TP-S17 and TS-S17 batches at the various storage conditions.

7.2.3.4 Drug assay

Assay or drug content of all samples was analyzed using the Jasco UV spectrophotometer. 2ml of the sample to be analyzed was taken in a separating funnel. To this, 10ml of 20% sodium hydroxide AR solution was added. The mixture was extracted using 10ml petroleum ether AR. The layers were allowed to separate for 10mins and then the yellow aqueous layer was separated. 2ml of this yellow layer was diluted further to 10ml with distilled water. The readings of the diluted samples were read at 302nm on Jasco UV spectrophotometer. All samples were scanned from 200-800nm to look out for any additional peaks or degradants occurring during stability testing. Any peak other than the ones observed at 258nm, 302nm and 372nm (of methotrexate) were recorded as degradant products during stability testing. All the readings were taken in triplicate and the average values with SEM within them were calculated.

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Results of drug content are tabulated in Tables 7.7 and 7.8.

7.2.3.5 Entrapment efficiency

Entrapment efficiency was determined for both lipids at 1, 3 and 6 months at all the four stability testing conditions and additional 9 and 12 months for refrigeration and 25ï‚°C/60% RH.

Entrapment efficiency was determined at 302nm on Jasco UV spectrophotometer. 1ml of the sample was filtered in a syringe filter of 0.22 The lipid thus separated was washed with 1ml of water to remove any drug adsorbed on the lipid surface. To the separated lipid, 10ml petroleum ether AR and 10ml 20% sodium hydroxide solution were added. The layers were allowed to separate. 2ml of MTX-SLN was also extracted with 10ml of petroleum ether and 10ml of 20% sodium hydroxide solution and the layers were allowed to separate. After separation, 2ml of aqueous layer of each sample was diluted to 10ml with distilled water and absorbance of both the aqueous layers was read at 302nm on the Jasco UV spectrophotometer.

Entrapment efficiency was calculated using the following formula:

% Entrapment efficiency = Amount of drug in mg in lipid layer x 100

Total drug added in mg

Results of entrapment efficiency are tabulated in Tables 7.9 and 7.10. Figure 7.8 represents the comparative % loss of entrapment efficiency of TP-S17 and TS-S17 batches at the various storage conditions.

7.3 RESULTS AND DISCUSSION

7.3.1 Physicochemical evaluation

The initial appearance of the MTX-SLNs was pale yellow with uniform texture.

No change in the appearance was observed under refrigeration and at 25ï‚°C/60% RH up to 12 months in both the lipid formulations, TP-S17 and TS-S17. In case of TP-S17 MTX-SLNs at 30ï‚°C/65% RH small agglomerated particles started appearing within 2 months of storage and the agglomeration increased till the end of 6 months. In case of 40ï‚°C/75% RH, this phenomenon was initiated within a month. This could be due to high storage temperature which causes melting and subsequent changes in the lipid structure leading to agglomeration of the nanoparticles.

In case of TS-S17 MTX-SLNs, the agglomeration was slower than that observed with TP MTX-SLNs. At 30ï‚°C/65% RH and 40ï‚°C/75% RH, small particles started appearing only after 2 months of storage as compared to TP-S17 where the process was initiated within a month at 40ï‚°C/75% RH. This could be probably due to larger carbon chain C16 in TS as compared to C14 in TP, which provides greater stability to TS. Hence TS-S17 MTX-SLNs showed lesser aggregation than TP-S17 MTX-SLNs.

Table 7.1 Physicochemical evaluation of TP-S17 MTX-SLNs at various storage conditions

Time in months

Storage condition

Refrigeration

25ï‚°C/60% RH

30ï‚°C/65% RH

40ï‚°C/75% RH

Initial

Pale yellowish dispersion with uniform texture

1

No change

No change

No change

Small particles on sides of vial

2

No change

No change

Small aggregated particles on sides of vial

Small aggregated particles on sides of vial

3

No change

No change

Slight aggregates on sides of vial

Aggregates on sides and slight yellow drug at bottom of vial

6

No change

No change

Aggregates on sides of vial with yellow drug at bottom of vial

Non-uniform particles and aggregates throughout the vial with pale yellow drug at bottom of vial

9

No change

No change

-

-

12

No change

No change

-

-

Table 7.2 Physicochemical evaluation of TS-S17 MTX-SLNs at various storage conditions

Time in months

Storage condition

Refrigeration

25ï‚°C/60% RH

30ï‚°C/65% RH

40ï‚°C/75% RH

Initial

Pale yellowish dispersion with uniform texture

1

No change

No change

No change

No change

2

No change

No change

Tiny particles on sides of vial

Tiny particles on sides of vial

3

No change

No change

Particles with slight aggregates

Slight aggregates on sides of vial and lesser yellowish drug layer than with TP MTX-SLNs

6

No change

No change

Pale yellow drug at bottom of vial with aggregates on sides of vial

Aggregates on sides and some on bottom of vial with pale yellow drug layer at bottom of vial

9

No change

No change

-

-

12

No change

No change

-

-

7.3.2 pH

The initial pH of the TP-S17 MTX-SLNs was 5.98. In case of the refrigerated control, it dropped gradually to 5.77 at the end of 12 months. At 25ï‚°C/60% RH, the pH dropped to a low of 5.73 at the end of 12 months. Methotrexate is acidic in nature and with time, there is slight oozing out of the drug into the external phase. Hence, the pH drops and with an increase in the temperature, drug oozing is faster and pH drop is higher. At 30ï‚°C/65% RH and 40ï‚°C/75% RH, pH dropped to 5 and 4.64 respectively at the end of 6 months.

TS-S17 MTX-SLNs showed an initial pH of 6.06. The refrigerated control showed a drop to 5.89 at the end of 12 months. In case of 25ï‚°C/60% RH, the pH was 5.87 at the end of 12 months, whereas at 30ï‚°C/65% RH and 40ï‚°C/75% RH, pH was 5.05 and 4.98 respectively at the end of 6 months. This behavior could again be due to the larger C16 carbon chain in TS as compared to C14 in TP, which binds methotrexate to a larger extent and does not allow it to ooze out of the lipid matrix into the external phase. Thus probably due to better retention of drug in lipid matrix of TS-S17 MTX-SLNs, the pH drop was lower in these batches at all the storage conditions as compared to those observed for TP-S17 MTX-SLNs.

Table 7.3 pH of TP-S17 MTX-SLNs at various storage conditions

Time in months

Storage condition

Refrigeration

25ï‚°C/60% RH

30ï‚°C/65% RH

40ï‚°C/75% RH

0

5.98

5.98

5.98

5.98

1

5.95

5.93

5.28

5.24

2

5.88

5.92

5.12

4.99

3

5.82

5.84

5.08

4.94

6

5.81

5.77

5

4.64

9

5.79

5.75

 -

- 

12

5.77

5.73

-

-

Table 7.4 pH of TS-S17 MTX-SLNs at various storage conditions

Time in months

Storage condition

Refrigeration

25ï‚°C/60% RH

30ï‚°C/65% RH

40ï‚°C/75% RH

0

6.06

6.06

6.06

6.06

1

6.03

6.01

5.38

5.22

2

5.99

5.97

5.24

5.19

3

5.96

5.95

5.13

5.05

6

5.95

5.93

5.05

4.98

9

5.92

5.9

-

-

12

5.89

5.87

-

-

Figure 7.1 pH of TP-S17 MTX-SLN Figure 7.2 pH of TP-S17 MTX-SLN

and TS-S17 MTX-SLN in control and TS-S17 MTX-SLN at 25ï‚°C/60% refrigeration RH

Figure 7.3 pH of TP-S17 MTX-SLN Figure 7.4 pH of TP-S17 MTX-SLN

and TS-S17 MTX-SLN at 30ï‚°C/65% and TS-S17 MTX-SLN at 40ï‚°C/75% RH RH

Figure 7.5 pH of TP-S17 MTX-SLN at Figure 7.6 pH of TS-S17 MTX-SLN at

all storage conditions of stability all storage conditions of stability studies studies

7.3.3 Particle Size Analysis

In case of both TP-S17 and TS-S17 MTX-SLNs the unimodal as well as multimodal size distribution did not show any significant increase (p>0.05) at any of the storage conditions except at 40ï‚°C/75% RH (p<0.05). Thus, both TP-S17 and TS-S17 MTX-SLNs were found to be stable in terms of particle size distribution at refrigeration, 25ï‚°C/60% RH and 30ï‚°C/65% RH. At 40ï‚°C/75% RH, aggregation of particles occurs which is reflected in the multimodal size distribution which shows a considerable increase of large particles to the size of almost a micron for TP-S17 MTX-SLNs (~44%) and TS-S17 MTX-SLNs (~41%). This can be observed in Figure 7.7.

7.3.4 Drug content

No additional drug peak was detected in the scans during the entire period of study at any of the stability conditions tested. Drug content was found to decrease over time at all the stability conditions tested. The data was evaluated statistically by applying one way ANOVA with Dunnett's t-test by comparing initial assay value against all the storage conditions over the period of time tested.

In case of MTX-SLNs of both TP and TS, there was no significant difference (p>0.05) from the initial value in case of refrigeration and 25ï‚°C/60% RH over the period of 12 months. No significant difference (p>0.05) was seen at 30ï‚°C/65% RH and 40ï‚°C/75% RH at 1 month in case of both lipids. However in case of TP-S17 MTX-SLNs at 30ï‚°C/65% RH and 40ï‚°C/75% RH, significant difference (p<0.01) was observed at all time points after 1 month storage. TS-S17 MTX-SLNs showed no significant difference (p>0.05) at 30ï‚°C/65% RH for 1 month. At the remaining time points, a significant difference (p<0.01) was observed at 30ï‚°C/65% RH and in case of 40ï‚°C/75% RH, a significant difference (p<0.01) was seen at all the time periods tested.

No degradation peak was observed at any time condition tested. Decrease in drug concentration over time may be due to breakdown of methotrexate or lipid. Methotrexate is reported to undergo photolytic and thermal decomposition at high pH and temperature conditions (Chatterji & Gallelli, 1978). At above pH 7 and 85ï‚°C, methotrexate hydrolyses and the hydrolysis rate increases rapidly above pH 9. Commercial parenteral methotrexate is stable up to 2 years when stored in its original vial at room temperature.

Thus MTX-SLNs of TP and TS stored as controls under refrigeration and at 25ï‚°C/60% RH did not exhibit any significant decrease over the period of testing (12 months).

Table 7.7 Drug content of TP-S17 MTX-SLNs at various storage conditions

ICH condition

% assay

Period in months

Initial

1

2

3

6

9

12

Control

Assay

99.13

100.21

101.24

100.91

101.84

98.96

98.78

101.07

100.14

101.37

100.65

99.03

99.31

100.41

100.52

101.68

101.25

101.90

98.09

100.45

100.25

Average ± SE

100.24 ± 0.575

100.68 ± 0.503

101.29 ±0.041

101.15 ±0.379

99.65 ±

1.125

99.57 ±0.45

99.81 ± 0.519

25ï‚°C/60% RH

Assay

99.13

99.13

100.24

97.70

100.58

97.76

98.69

101.07

100.51

100.91

99.12

98.92

98.55

99.36

100.52

100.41

100.54

99.18

98.35

99.16

98.35

Average

100.24

100.02

100.56

98.67

99.28

98.49

98.80

SEM

0.575

0.442

0.194

0.482

0.669

0.406

0.298

30ï‚°C/65% RH

Assay

99.13

100.65

96.22

91.34

85.93

101.07

99.18

97.38

90.42

86.68

100.52

97.46

96.32

90.62

89.04

Average

100.24

99.10

96.64

90.79

87.21

SEM

0.575

0.922

0.371

0.278

0.936

40ï‚°C/ 75% RH

Assay

99.13

97.29

97.42

86.27

83.84

101.07

97.40

95.73

89.09

84.66

100.52

98.75

94.67

88.96

85.39

Average

100.24

97.81

95.94

88.11

84.63

SEM

0.575

0.468

0.8

0.919

0.446

Table 7.8 Drug content of TS-S17 MTX-SLNs at various storage conditions

ICH condition

Period in months

Initial

1

2

3

6

9

12

Control

Assay

100.02

100.39

101.84

101.67

102.86

100.90

100.66

99.92

99.00

102.15

100.84

101.39

98.75

99.37

101.13

99.86

101.16

98.11

99.37

99.80

98.80

Average

100.36

99.75

101.72

100.21

101.21

99.82

99.61

SEM

0.387

0.404

0.293

1.074

1.014

0.619

0.552

25ï‚°C/ 60% RH

Assay

100.02

98.94

98.62

102.32

96.58

100.24

99.31

99.92

99.89

99.45

99.74

97.47

98.88

100.74

101.13

101.06

101.35

101.00

100.21

99.38

99.18

Average

100.36

99.96

99.81

101.02

98.09

99.50

99.74

SEM

0.387

0.611

0.807

0.745

1.092

0.396

0.500

30ï‚°C/ 65% RH

Assay

100.02

100.90

97.28

94.95

89.56

99.92

99.21

97.05

92.24

90.52

101.13

100.85

95.68

94.91

87.94

Average

100.36

100.32

96.67

94.03

89.34

SEM

0.387

0.556

0.5

0.897

0.753

40ï‚°C/ 75% RH

Assay

100.02

98.00

92.54

89.25

85.17

99.92

96.35

92.11

88.94

86.07

101.13

95.31

94.80

89.64

86.73

Average

100.36

96.55

93.15

89.28

85.99

SEM

0.387

0.781

0.836

0.202

0.452

7.3.5 Entrapment efficiency

The initial entrapment efficiency of TP-S17 MTX-SLNs was 75.68% which dropped significantly (p<0.05) to 71.71% and 70.51% at 12 months respectively in samples stored under refrigeration and 25ï‚°C/60% RH. A sharp and significant decrease (p<0.05) was observed at 30ï‚°C/65% RH and 40ï‚°C/75% RH at all the time points tested. At higher temperatures, melting of lipid takes place and drug oozes out lowering the entrapment efficiency. This was confirmed from the lowering of pH at higher temperature storage conditions because methotrexate is an acidic drug and when it oozes out of the lipid matrix, there is a fall in pH.

In case of TS-S17 MTX-SLNs, significant drop in the entrapment efficiency (p<0.05) was observed at 30ï‚°C/65% RH and 40ï‚°C/75% RH at all the time points tested. The decrease at refrigerated condition and 25ï‚°C/60% RH was not significant during the period of 12 months. This is because TS is a higher carbon chain fatty acid molecule (C16) as compared to TP (C14). Hence the drug remains better encapsulated in the lipid matrix and does not ooze out which was confirmed by the relatively low fall in pH values.

As seen from Figure 7.8, the % loss of entrapment efficiency is higher in TP-S17 at all storage conditions than that observed in TS-S17.

Table 7.9 Entrapment efficiency of TP-S17 MTX-SLNs at various storage conditions

ICH condition

Period in months

Initial

1

3

6

9

12

Control

Average

75.68

74.50

75.67

73.93

72.87

71.71*

SEM

0.757

0.745

0.757

0.739

0.729

0.717

% Loss in EE

1.56

0.01

2.31

3.71

5.25

25ï‚°C/60% RH

Average

75.68

73.66

73.99

72.62

72.81

70.51*

SEM

0.757

0.737

0.740

0.726

0.728

0.705

% Loss in EE

2.67

2.23

4.04

3.79

6.83

30ï‚°C/65% RH

Average

75.68

68.83*

65.90*

56.02*

SEM

0.757

0.688

0.659

0.560

% Loss in EE

9.05

12.92

25.98

40ï‚°C/75% RH

Average

75.68

66.68*

57.74*

38.01*

SEM

0.757

0.667

0.577

0.380

% Loss in EE

11.89

23.71

49.78

Table 7.10 Entrapment efficiency of TS-S17 MTX-SLNs at various storage conditions

ICH condition

Period in months

Initial

1

3

6

9

12

Control

Average

81.84

81.60

81.33

81.34

80.30

79.93

SEM

0.818

0.816

0.813

0.811

0.803

0.799

% Loss in EE

0.29

0.62

0.61

1.88

2.33

25ï‚°C/ 60% RH

Average

81.84

81.81

80.94

80.61

80.23

78.96

SEM

0.818

0.818

0.809

0.806

0.802

0.790

% Loss in EE

0.04

1.10

1.50

1.97

3.52

30ï‚°C/ 65% RH

Average

81.84

76.22*

67.10*

63.32*

SEM

0.818

0.762

0.671

0.633

% Loss in EE

6.87

18.01

22.63

40ï‚°C/ 75% RH

Average

81.84

67.91*

61.17*

47.64*

SEM

0.818

0.679

0.612

0.476

% Loss in EE

17.02

25.26

41.79

Figure 7.8 represents the comparative % loss of entrapment efficiency of TP-S17 and TS-S17

The CDER Guidance Q1E explains Evaluation of Stability Data (Guidance for Industry Q1E Evaluation of Stability Data, 2004) According to these guidelines, for new drug products intended to be stored in a refrigerator; when there is no significant change at the accelerated condition of testing, the proposed re-test period or shelf life can be up to one-and-a-half times as long as, but not more than 6 months beyond. Accordingly, as per these guidelines, a shelf life of 18 months under refrigeration can be assigned to the new drug product.

Thus, both tripalmitin and tristearin solid lipid nanoparticles were found to be stable under refrigeration and at accelerated stability condition of 25ï‚°C/60% RH for 12 months and were assigned a shelf life of 18 months under refrigeration as per the CDER Guidance Q1E. However, tristearin solid lipid nanodispersions were found to exhibit better stability at accelerated stability testing conditions as compared to tripalmitin solid lipid nanodispersions.