Stability of Soft Gelatin Capsules Containing Thick ...medicina.lsmuni.lt/med/11p2/11p2-05e.pdfStability of Soft Gelatin Capsules Containing Thick Extract of Pine Needles Stability

71

Medicina (Kaunas) 2011;47(Suppl 2)

Medicina (Kaunas) 2011;47(Suppl 2):71-7

Stability of Soft Gelatin Capsules Containing Thick Extract of Pine Needles

Irena Daberte1, Ilze Barene1, Juris Rubens2, Maris Daugavietis3, Natalia Sazhenova1

1Department of Dosage Forms Technology, Riga Stradins University, Latvia, 2BF-esse, Ltd., Riga, Latvia, 3Latvia State Forestry Research Institute “Silava,” Salaspils, Latvia

Key words: thick extract of pine needles; stability studies; soft gelatin capsules; disintegration time; content of carotenes.

Summary. The aim of the study was to investigate the stability of the developed dosage form – soft gelatin capsules containing the thick extract of pine needles. The impact of package type and storage conditions on the quality of capsules was investigated.

Material and Methods. The laboratory batch of soft gelatin capsules was prepared using a dip-ping method. Three pilot batches and two manufacturing batches were prepared by a stamping method. The capsules were estimated for appearance, uniformity of mass, disintegration time, and content of carotenes. The stability studies were performed at 25ºC±2ºC/60%±5% relative humidity and 30ºC±2ºC/65%±5% relative humidity.

Results. The content of carotenes in one pilot batch was below the level required in the quality specification. The content of carotenes in other pilot batches, laboratory batch, and manufacturing batches during the stability testing was satisfactory: not less than 30 mg%. Cross-linking of gelatin molecules in capsule shells during the disintegration test was observed.

Conclusions. The laboratory batch of soft gelatin capsules containing the thick extract of pine needles was qualitative during 24 months of stability study. The quality of capsules prepared by the stamping method depended on the preparation technology of the formulation for encapsulation. For the preparation of a qualitative final product, the active substance – thick extract of pine needles with a content of carotenes not less than 35 mg% – should be used. The stability of thick extract of pine needles was greater in soft gelatin capsules packed into plastic jars.

Adresas susirašinėti: I. Daberte, Department of Dosage Forms Technology, Riga Stradins University, Dzirciema 16, 1007 Riga, Latvia. El. paštas: [email protected]

Correspondence to I. Daberte, Department of Dosage Forms Technology, Riga Stradins University, Dzirciema 16, 1007 Riga, Latvia. E-mail: [email protected]

IntroductionThe purpose of stability study for pharmaceuti-

cal product is to establish the shelf life and storage conditions of the product (1). Two different types of stability studies are used: short-term and long-term studies, which allow predicting how the quality of active substance and fi nal product varies in time under the infl uence of a variety of environmental factors (2, 3). The primary data used to establish the shelf life of a product are the data from long-term stability studies (4, 5).

The stability evaluating models, design and ana-lyzing procedures of pharmaceutical products are described in the notes for the guidance on stability testing and evaluation of the stability data issued by the European Medicines Agency (EMA) (6, 7).

Herbal medicinal products contain different ac-tive substances and their combinations. In case of a herbal medicinal product containing a herbal sub-stance or herbal preparation with constituents of the known therapeutic activity, the variation in content during the proposed shelf life should not exceed ±5% of declared assay value. In case of a herbal medicinal product containing a herbal substance

or herbal preparation where constituents with the known therapeutic activity are unknown, a variation in marker content during the proposed shelf life of ±10% of initial assay value can be accepted (8, 9).

A thick extract produced from pine needles con-tains carotenoids, chlorophyll, polyprenols, vita-mins, phytosterols, etc. (10). The thick extract of pine needles (TEPN) has a reparative infl uence on experimental gastric ulcer, bactericidal effect, anti-oxidant effect, and weak immune modulating effect. The main indications for use are chronic active gas-tritis, chronic gastroduodenal ulcer, and dyspepsia (11–14). Soft gelatin capsules (SGCs) with TEPN were developed for prevention and treatment of gas-trointestinal diseases.

The aim of this study was to investigate the sta-bility of dosage form – soft gelatin capsules contain-ing the thick extract of pine needles.

Material and MethodsTEPN containing moisture and volatile sub-

stances not more than (NMT) 10% was used as an active substance. Gelatin, glycerol, methyl parahy-droxybenzoate, and purifi ed water were used for the

72


preparation of SGCs. The formulations for fi lling SGCs were prepared using vegetable oils (arachis and sunfl ower oil) and an emulsifying agent – glyc-erol monooleate. The fi lled capsules were washed with isopropyl alcohol or ethanol. Petrol and alu-minium oxide were used for the assay method.

Preparation of Formulations Containing Thick Extract of Pine Needles. The emulsifying agent was melted and mixed with vegetable oil at 45°C–50°C in a stainless steel vessel. TEPN was heated up to 45°C–50°C and added to the mixture of vegetable oil and emulsifying agent, and stirred until homog-enous mass was achieved. The speed for mixing the components of fi lling mass for the pilot batch 1 was 300–500 rpm, for other pilot batches and manufac-turing batches – 25–30 rpm.

Preparation of Capsules. The laboratory batch of SGCs was prepared using the dipping method. The formulation containing 30% TEPN, 65% arachis oil, and 5% glycerol monooleate in 1 g (300 mg of TEPN) was fi lled into capsules. Three pilot batches and two manufacturing batches of SGCs were pre-pared using the stamping method at the enterprise using rotary die equipment (15). The formulation containing 50% TEPN, 45% sunfl ower oil, and 5% glycerol monooleate in 600 mg (300 mg of TEPN) was fi lled into capsules.

Primary Packaging. The SGCs of the laboratory batch were packed into plastic jars. The packaging for the pilot batches and manufacturing batches was as follows:

Aluminium foil and polyvinylchloride fi lm blis-ters (Al/PVC blisters) for the pilot batch 1, the pilot batch 3, and the manufacturing batch 1;

Plastic jars for the pilot batch 2 and the manu-facturing batch 2.

Analysis of Capsules. The capsules were estimat-ed for their appearance, uniformity of mass, disinte-gration time, and content of carotenes.

The uniformity of mass of capsules was evalu-ated according to the European Pharmacopoeia (Ph. Eur.) 6.0, vol. 1, 2.9.5 (16). Twenty capsules ran-domly selected from each batch were used for the test. Electronic balance type ABS 220-4 (KERN & Sohn GmbH, Germany) was used. The deviation from average mass of capsules must be NMT ±7.5%.

The disintegration time of prepared capsules was evaluated according to Ph. Eur. 6.0, vol. 1, 2.9.1 (16). Six capsules randomly selected from each batch were used for the test. The disintegration medium was purifi ed water maintained at 37°C±0.5°C. The dis-integration time of capsules must be NMT 30 min.

Column chromatography was used for the isola-tion of carotenes and visible absorption spectropho-tometry for the assay of carotenes. For estimation of carotene content in the prepared capsules containing TEPN formulation, at fi rst carotenes were isolated

from accurately weighed capsule fi lling of approxi-mately 500 mg. The capsule fi lling was mixed with petrol and fi ltered, and the petrol solution was sepa-rated through an aluminium oxide column. The as-say of isolated carotenes in an eluate was performed spectrophotometrically at 450 nm wavelength using a UV-visible spectrophotometer (Nicolet Evolution 100, Thermo Electron Corporation) (17, 18). The content of carotenes must be not less than (NLT) 30 mg% in accordance with the requirements of the quality specifi cation.

Stability. Long-term and accelerated stability studies for laboratory batch and pilot batches were conducted at 25°C±2°C and 30°C±2°C. The manu-facturing batches were stored in climatic chambers at 25°C±2°C/60%±5% RH and at 30°C±2°C/65%±5% RH (6, 7). The analyses were performed after 3, 6, 9, 12, 18, and 24 months for long-term stability study and after 3, 6, 9, and 12 months for accelerated sta-bility study. The stability studies of the pilot batches 2 and 3 and manufacturing batches are being con-tinued.

Statistical analysis of the data was conducted us-ing the MS Offi ce Excel 2007 software. The linear regression analysis was used for the stability study (19), with calculations of regression equation and determination coeffi cient.

ResultsStability of Soft Gelatin Capsules of the Laboratory

Batch. During the long-term stability and acceler-ated stability testing, the appearance of SGCs of laboratory batch was in accordance with the require-ments of the quality specifi cation, and uniformity of SGC mass was in accordance with the requirements of Ph. Eur. The initial content of carotenes in SGCs of laboratory batch was 38.94 mg% and disintegra-tion time 8–10 min. After 24 months of long-term stability testing, the content of carotenes was 30.12 mg% and disintegration time was 15–18 min; af-ter 12 months of accelerated stability testing, it was 35.34 mg% and 20–24 min, respectively (Fig. 1).

Stability of Soft Gelatin Capsules of the Pilot Batches. The appearance of SGCs of all pilot batch-es was in accordance with the requirements of the quality specifi cation, and the mass uniformity of SGCs of all pilot batches during the stability testing was in accordance with the requirements of Ph. Eur.

The initial quality of the pilot batch 1, for which the fi lling components were mixed with the high-speed mixer, was not satisfactory: the content of carotenes was under the required level – 22.03 mg% (Fig. 2). The content of carotenes of other pilot batches prepared using the slow mixing of fi lling mass, during the stability testing, was NLT 30 mg% (Fig. 3). The disintegration time of capsules of all pilot batches was satisfactory (Fig. 2, 3).

Irena Daberte, Ilze Barene, Juris Rubens, et al.

73



Stability of Soft Gelatin Capsules of the Manufac-turing Batches. The content of carotenes in SGCs of manufacturing batches during the stability testing was NLT 30 mg% (Fig. 4).

The appearance and disintegration time of SGCs of manufacturing batches stored in the climatic cham-bers depended on packaging and storage conditions.

Only the SGCs packed in the plastic jars dur-ing the long-term stability testing did not show any changes in appearance. After 6 months of storage during the accelerated stability testing in plastic jars and during the long-term stability testing in Al/PVC blisters, the shells of capsules were soft. After 6 months of storage during the accelerated stabil-ity testing in Al/PVC blisters, the shells of capsules were very soft and swollen.

During the stability study of SGCs of manufac-turing batches, the disintegration test showed that disintegration time in water was greater for capsules packed in Al/PVC blisters and for capsules stored under stress conditions 30°C±2°C/65%±5% RH (Figs. 4 and 5).

The disintegration time of capsules stored in Al/PVC blisters under stress conditions 30°C±2°C/ 65%±5% RH for 6 months was tested in a simulated intestinal fl uid (phosphate buffer solution, pH 6.8, with pancreas powder) (16). The disintegration time of capsules was in accordance with the requirements of Ph. Eur.: the fi lling of capsules disintegrated in 15 min, the capsule shells completely disintegrated in 20 min.

Estimation of Shelf Life of TEPN Soft Gelatin Capsules. The results of the stability study for 24 months of SGC laboratory batch were used as a shelf life estimation model (Fig. 6). A linear regression equation was used for the calculation of carotene content in active substance – TEPN for preparation of a qualitative fi nal product:

a=y–b×x=27–(–0.9793×8)=34.83 mg%≈35 mg%.

The quality of the pilot batches 2 and 3 and manufacturing batches was in accordance with the requirements of the quality specifi cation (the con-tent of carotenes ranged from 36.36 to 41.89 mg%).

Fig. 1. Stability of soft gelatin capsules of the laboratory batch

Long-term

Accelerated

Reglamented, NLT

0 3 6 9 12 18 24Duration of Storage, Months

454035302520151050

Con

tent

of C

arot

enes

, mg%

Long-term

Accelerated

Reglamented, NMT

0 3 6 9 12 18 24Duration of Storage, Months

35

30

25

20

15

10

5

0

Disi

nteg

ratio

n T

ime,

min

Long-term

Accelerated

Reglamented, NLT

0 3 6 9 12Duration of Storage, Months

Con

tent

of C

arot

enes

, mg%

Long-term

Accelerated

Reglamented, NMT35

30

25

20

15

10

5

0

Disi

nteg

ratio

n T

ime,

min

35

30

25

20

15

10

5

0

Duration of Storage, Months0 3 6 9 12

Fig. 2. Stability of soft gelatin capsules of the pilot batch 1

74


2nd Batch, Long-term2nd Batch, Accelerated3rd Batch, Long-term3rd Batch, AcceleratedReglamented, NLT

0 3 6 9Duration of Storage, Months

50

40

30

20

10

0

Con

tent

of C

arot

enes

, mg%

2nd Batch, Long-term2nd Batch, Accelerated3rd Batch, Long-term3rd Batch, AcceleratedReglamented, NMT

35

30

25

20

15

10

5

0

Disi

nteg

ratio

n T

ime,

min

0 3 6 9Duration of Storage, Months

Fig. 3. Stability of soft gelatin capsules of the pilot batches 2 and 3

1st Batch, Long-term1st Batch, Accelerated2nd Batch, Long-term2nd Batch, AcceleratedReglamented, NLT

1st Batch, Long-term1st Batch, Accelerated2nd Batch, Long-term2nd Batch, AcceleratedReglamented, NMT

0 3 6Duration of Storage, Months

0 3 6Duration of Storage, Months

40

35

30

25

20

15

10

5

0

Disi

nteg

ratio

n T

ime,

min

40

35

30

25

20

15

10

5

0

Con

tent

of C

arot

enes

, mg%

Fig. 4. Stability of soft gelatin capsules of the manufacturing batches

DiscussionThe physical and chemical stability of pharma-

ceutical products is of great importance (3). The ac-tive substances of TEPN (carotenoids, chlorophylls, etc.) are relatively unstable under infl uence of dif-ferent environmental factors, such as temperature, oxygen, and light. However, these substances play an important role in biological activity of TEPN and its dosage form, and this active complex must be stable during the time of storage, transporting, and use of pharmaceutical product.

The assay is the most important index that testi-fi es the quality of a pharmaceutical product. In our study, one pilot batch showed the initial content of carotenes under the required level. Such a difference in the quality of capsules may be explained by mixing rate of the fi lling mass. During the mixing process of

the pilot batch 1 capsules fi lling mass in a high-speed mixer, molecular oxygen caused the oxidation pro-cess of carotenes (3). Therefore, SGCs of other pilot batches and manufacturing batches were prepared us-ing the slow mixing of the fi lling mass of capsules.

The appearance is one of the indicators show-ing the changes in the quality of a pharmaceutical product. During the stability testing, the appearance of capsules containing TEPN depended on primary packaging and storage conditions.

For absorption and effect on body, the active substances must release from dosage form fi rst; therefore, it is important to estimate its disintegra-tion time. During the stability study of SGCs of manufacturing batches stored in climatic chambers, the disintegration test showed that the disintegration time of capsules in water also depended on primary


75


Fig. 5. Disintegration of soft gelatin capsules in water at 37°C after storage in climatic chambers for 6 months Al/PVC blisters, aluminium foil and polyvinylchloride fi lm blisters; RH, relative humidity.

Plastic jars, 25°C±2°C and 60%±5% RH

5 min 10 min 15 min

5 min 10 min 15 min 20 min

Al/PVC blisters, 25°C±2°C and 60%±5% RH


Plastic jars, 30°C±2°C and 65%±5% RH

Al/PVC blisters, 30°C±2°C and 65%±5% RH


Fig. 6. Linear regression of carotene content and disintegration time of soft gelatin capsules of the laboratory batch during the long-term stability study

Reglamented Content of CarotenesLower Acceptance CriterionLinear, Content of Carotenes

0 3 6 9 12 18 21 24Duration of Storage, months

45

40

35

30

25

20

15

10

5

0

Con

tent

of C

arot

enes

, mg%

y=–0.9793x+38.94R2=0.9699

0 3 6 9 12 18 21 24Duration of Storage, months

35

30

25

20

15

10

5

0

Disi

nteg

ratio

n T

ime,

min

Reglamented Disintegration TimeLinear, Disintegration Time

y=0.7405x+10R2=0.8383


76


packaging and storage conditions. The disintegration time was greater for the capsules packed in Al/PVC blisters and stored under stress conditions. It could be explained by phenomenon known as gelatin cross-linking, which is common to gelatin as a polymer. Aldehydes (also in TEPN) react with ε-amino groups (mainly lysine) and built cross-sites in a gelatin mole-cule (20, 21). This process results in the formation of swollen, rubbery water-insoluble membranes known as pellicles during disintegration testing. The pelli-cles surround the fi ll or the capsule and prevent the fi ll from being released. This process is accelerated at high temperature and humidity (22). In such cases, the disintegration test can be conducted in a simu-lated intestinal fl uid with enzymes (16, 23).

Conclusions1. The laboratory batch of soft gelatin capsules con-

taining thick extract of pine needles was qualita-tive during the stability study for 24 months.

2. The quality of capsules prepared by rotary die method depended on the preparation technology of formulation for encapsulation.

3. The stability of thick extract of pine needles was greater in soft gelatin capsules packed into plas-tic jars.

4. For the preparation of qualitative fi nal product, the active substance – thick extract of pine nee-dles with content of carotenes NLT 35 mg% – should be used.

5. Two-year shelf life for soft gelatin capsules con-taining the thick extract of pine needles is pre-dictable.

AcknowledgmentsThis research was supported by the European

Social Fund.

Statement of Conflict of InterestThe authors state no confl ict of interest.

Minkštųjų želatinos kapsulių, turinčių tirštojo pušų spyglių ekstrakto, stabilumas

Irena Daberte1, Ilze Barene1, Juris Rubens2, Maris Daugavietis3, Natalia Sazhenova1

Rygos Stradins universiteto Vaistų formos technologijos katedra, 2BF-esse, Ltd., Ryga, 3Valstybinis Latvijos miškininkystės tyrimų institutas „Silava“, Salaspilis, Latvija

Raktažodžiai: tirštasis pušų spyglių ekstraktas, stabilumo tyrimai, minkštosios želatinos kapsulės, suiri-mo laikas, karotenų kiekis.

Santrauka. Tyrimo tikslas. Ištirti vaistui suteiktos dozuotos formos – minkštųjų želatinos kapsulių, turinčių tirštojo pušų spyglių ekstrakto, stabilumą. Taip pat tirta pakuotės tipo bei laikymo sąlygų įtaka kapsulių kokybei.

Tyrimo medžiaga ir metodai. Laboratorinė minkštųjų želatinos kapsulių partija buvo paruošta lašelių metodu. Trys bandomosios ir dvi gamybai skirtos partijos buvo paruoštos štampavimo metodu. Įvertinta kapsulių išvaizda, masės vientisumas, suirimo laikas ir karotenų kiekis. Šie stabilumo tyrimai atlikti esant 25±2°C/60±5 proc. ir 30±2°C/65±5 proc. santykiniam drėgnumui.

Rezultatai. Karotenų kiekis vienoje bandomojoje partijoje buvo mažesnis nei reikalaujama nurodytose kokybės sąlygose. Karotenų kiekis kitose bandomosiose partijose, laboratorinėje partijoje ir gamybai skir-tose partijose stabilumo tyrimo metu buvo patenkinamas: ne mažiau kaip 30 mg%. Atliekant suirimo laiko testą, pastebėtas želatinos molekulių kryžminių jungčių susidarymas kapsulių apvalkaluose.

Išvados. Laboratorinė minkštųjų želatinos kapsulių, turinčių tirštojo pušų spyglių ekstrakto, partija išliko kokybiška per 24 stabilumo tyrimo mėnesius. Kapsulių, paruoštų štampavimo metodu, kokybė priklausė nuo kapsulės pripildymo technologijos. Norint paruošti kokybišką galutinį produktą, reikia panaudoti aktyviąją medžiagą – tirštąjį pušų spyglių ekstraktą, kuriame būtų ne mažiau kaip 35 mg% karotenų. Tirštojo pušų spyglių ekstrakto stabilumas didesnis minkštosiose želatinos kapsulėse, supakuotose į plastikinius indus.

References1. Chow SC, Shao J. Statistics in drug research: methodologies

and recent developments. New York: Marcel Dekker, Inc.; 2002. p. 77-106.

2. Pugh J. Kinetics and product stability. In: Aulton ME, editor. Pharmaceutics: The science of Dosage Form Design. 2nd ed. Edinburgh: Churchill & Livingston; 2002. p. 109-12.

3. Waterman KC, Adami RC. Accelerated aging: prediction

of chemical stability of pharmaceuticals. Int J Pharm 2005; 293:101-25.

4. Komka K, Kemeny S. A modifi ed error model for the as-sessment of stability of pharmaceutical products. Chemo-metrics and Intelligent Laboratory Systems 2004;72:161-5.

5. Chow SC. Statistical design and analysis of stability studies. Chapman & Hall/CRC, Taylor & Francis Group; 2007. p.


77


13-26.6. Guideline on Stability Testing of New Active Substances

and Products. CPMP/ICH/2736/99.7. Guidance on Evaluation of Stability Data. CPMP/ICH/

420/02.8. CPMP/QWP/2819/00 rev 1. EMEA/CVMP/814/00 rev

1. 30 March 2006. Guideline on quality of herbal medicinal products / Traditional herbal medicinal products.

9. EMEA/HMPC/CHMP/CVMP/214869/2006. Guideline on quality of combination herbal medicinal products/tradi-tional herbal medicinal products.

10. Pavlutskaya I, Roschin V, Solovyov V. Gruppovoi sostav chlorofi lo-karotinovoi pasty i provitaminnogo koncentrata iz chvoinoi drevesnoi zeleni. (Group structure of chloro-phyll-carotene paste and provitamin concentrate from co-nifer foliage greenery.) Chemistry of Wood 1984;6:109-12.

11. Rubens J, Kuzņecovs S, Daugavietis M, Seļezņovs J. Fites-tēna reparatīvo un baktericīdo īpašību izpēte. (Investigation of Fitesten reparative and bactericidal properties.) Latvijas Ārsts 1990;5:41-4.

12. Rubens J, Seļezņovs J, Kleina R, Pokrotnieks J. Fitestēna klīniskā aprobācija. (Clinical approbation of Fitesten.) Lat-vijas Ārsts 1995;4:16-9.

13. Rubens J, Seļezņovs J. Koksnes zaļās masas pārstrādes pro-duktu antioksidanto īpašību izpēte. (Investigation of anti-oxidant properties of processing products of tree foliage.) Lat vijas Ārsts 1995;8:35-7.

14. Seleznov J, Kuznetsov S, Rubens J, Orlikov G, Pokrotnieks J. Gastroprotektivnoje deistvije gustogo ekstrakta iz chvoi Pinus sylvestris L. i Picea abies (L.) Karst. (Gastro protective effect of thick extract of needles of Pinus sylvestris L. and

Picea abies (L.) Karst.) Rastitelnyje resursy 2001;37(1):63-9.15. Podczeck F. Technology to manufacture soft capsules. In:

Podczeck F, Jones BE, editors. Pharmaceutical capsules. 2nd ed. London: Pharmaceutical Press; 2004. p. 195-9.

16. European Pharmacopoeia. 6th ed. Vol. 1, 2. Strasbourg: Council of Europe; 2007. p. 263-5, 274, 278.

17. Konstantinova I, Artjuh M, Kulkevicha K. Primenenije fi ziko-khimiceskich metodov dla ocenki kachestva gustogo ekstrakta chvoi. (Application of physicochemical methods for assessment of quality of thick extract of needles.) Phar-macy. Research articles. Riga: RMI; 1989. p. 83-6.

18. Fruits, vegetables and derived products – Determination of carotene content – Part 2: Routine methods. International standard ISO 6558-2:1992(E).

19. Gardiner WP. Statistical analysis methods for chemists. Cambridge: The Royal Society of Chemistry; 1997. p. 168-226.

20. Singh S, Pakhale SP. Gelatin-containing formulations: changes in dissolution characteristics. In: Swarbrick J, edi-tor. Encyclopedia of pharmaceutical technology. 3rd ed. New York: Marcel Dekker, Inc.; 2007. p. 1861-74.

21. Digenis GA, Gold TB, Shah VP. Cross-linking of gelatin capsules and its relevance to their in vitro-in vivo perfor-mance. J Pharm Sci 1994;83(7):915-21.

22. Gennadios A. Soft gelatin capsules. In: Gennadios A, edi-tor. Protein-based fi lms and coatings. CRC Press; 2002. p. 393-443.

23. Marchais H, Cayzeele G, Legendre JY, Skiba M, Arnaud P. Cross-linking of hard gelatin carbamazepine capsules: ef-fect of dissolution conditions on in vitro drug release. Eur J Pharm Sci 2003;19:129-32.

Received 10 September 2010, accepted 14 July 2011Straipsnis gautas 2010 09 10, priimtas 2011 07 14


Documents

Stability of Soft Gelatin Capsules Containing Thick ...medicina.lsmuni.lt/med/11p2/11p2-05e.pdfStability of Soft Gelatin Capsules Containing Thick Extract of Pine Needles Stability