Solid State Compatibility between Silymarin and Tablet Excipients by Thermal and Non-Thermal Methods, its ph Stability and Solubility Analysis

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1 Research Article ISSN: *Corresponding author. Dr. Kanchan Kohli, Associate Professor, Dept of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India. Shamama Javed et al. / Journal of Pharmacy Research 2012,5(3), Available online through Solid State Compatibility between Silymarin and Tablet Excipients by Thermal and Non-Thermal Methods, its ph Stability and Solubility Analysis Shamama Javed, Kanchan Kohli*, Mushir Ali Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India Received on: ; Revised on: ; Accepted on: ABSTRACT In this study drug-excipient compatibility studies were carried out between silymarin and various tablet excipients and according to DSC, silymarin was found to be compatible with lactose, croscarmellose sodium, sodium starch glycolate, PVP k30, magnesium stearate, hydroxylpropylmethylcellulose, sodium lauryl sulphate. Interesting findings were observed with starch and microcrystalline cellulose ph 101 with splitting of drug characteristic peak. The incompatibilities were seen with crospovidone, methocel and aerosil where complete disappearance of drug peak occurred upon heating. FT-IR studies implied that except aerosil, all the other excipients were compatible with silymarin. In the solution state stability studies, silybin in silymarin was found to be stable in ph range of 1-7 and degradation at ph 9 was observed with the help of RP HPLC-UV data and in solubility studies, the maximum solubility was achieved with 2.0% sodium lauryl sulphate with solubility enhancement factor (σ) of fold. Concluding the fact that silymarin exhibits good compatibility with commonly used tablet excipients and is stable over a wide ph range and enhanced solubility in an anionic surfactant. Key words: Silymarin, Excipients, Compatibility, Differential Scanning Calorimetry, ph Stability, Solubility. 1.INTRODUCTION The choice of excipient for the formulation is of vital importance in ensuring (Table 1) were subjected to isothermal stress condition of 55 ºC for 3 weeks the stability and efficacy of the resulting preparations as excipients are as suggested by Van Dooren and Duphar. [5] Samples (10 mg) were accurately weighed and sealed in glass vials and kept in stability chamber. DSC integral component of almost all pharmaceutical dosage forms. Understanding the reactivity of the API in solid state when mixed with excipient is curves were obtained in Pyris 6 DSC equipment using aluminium crimp critical to commercial formulation development. [1] In determining the drugexcipient interaction, thermoanalysis offers significant advantages in saving 20ml/min) and at a heating rate of 10 ºC/min in temperature range from 30- cells with about 2 mg of samples, under dynamic N 2 atmosphere (flow rate: both time and substance. [2] Thus, DSC data can provide much information 300 ºC. as thermal transitions associated with the API can be observed. [3] The DSC Table 1: Different Classes of Tablet Excipients Used for DSC studies data must be supported with the non-thermal methods like FT-IR for confirmation. Silymarin is a complex chemical moiety consisting mainly of Class Excipient used Drug: Excipient silybin (A & B) and isosilybin (A & B), silychristin, silydianin, taxifolin and (55ºC for 3 weeks) quercetin obtained from Silybum marianum plant with well known hepatoprotective activity. [4] The present study was undertaken to establish the solid state compatibility of silymarin with commonly used tablet excipients using thermal and non-thermal methods, ph stability profile of silybin in buffered aqueous silymarin solution and the effect of sodium lauryl sulphate on solubility of silymarin (silybin). 2. MATERIALS AND METHODS Silymarin (70% standardized extract) was obtained as a gift sample from Maneesh Pharmaceuticals Ltd. Mumbai, India. The excipients like starch, croscarmellose sodium (Ac-Di-Sol), sodium lauryl sulphate (SLS), sodium starch glycolate (Explotab), cross-linked polyvinylpyrrolidone k30 (Crospovidone), microcrystalline cellulose (Avicel), methylcellulose (Methocel), magnesium stearate, hydroxypropylmethylcellulose (HPMC E5), polyvinylpyrrolidone (Kollidon 30) and colloidal silicon dioxide (Aerosil) were obtained from Arbro Pharmaceuticals Ltd. Kirti Nagar, New Delhi, India. HPLC grade solvents and Milli-Q water were used for analysis by HPLC and double distilled water was used throughout UV studies. All other chemicals and reagents were of analytical grade. 2.1 Sample preparation for DSC studies The silymarin alone and its 1:1 mixtures with various tablet excipients Diluent Microcrystalline Cellulose (MCC ph 101) 1:1 Lactose monohydrate 1:1 Binder Polyvinylpyrrolidone (Kollidon 30) 1:1 Cross-linked Polyvinylpyrrolidone (Crospovidone) 1:1 Hydroxypropylmethylcellulose (HPMC 5 cps) 1:1 Methylcellulose (Methocel) 1:1 Disintegrant Starch 1:1 Croscarmellose Sodium (Ac-Di-Sol) 1:1 Sodium Starch Glycolate (Explotab) 1:1 Lubricant Magnesium Stearate 1:1 Sodium Lauryl Sulphate 1:1 Glidant Colloidal Silicon Dioxide (Aerosil) 1:1 2.2 Sample preparation for FT-IR studies Silymarin alone and its 1:1 mixtures with various tablet excipients [Table 2], kept at 55 ºC for 3 weeks were subjected to FT-IR spectroscopy (Perkin Elmer). [5] Pellets of the samples were prepared after grinding and dispersing the powder in micronized IR grade KBr powder in a mortar and pestle, and scanned over a wave number range of cm -1 i.e. the fingerprint region. Table 2: Different Classes of Tablet Excipients Used for FT-IR studies Class Excipient used Drug: Excipient (55ºC for 3 weeks) Diluent Microcrystalline Cellulose (MCC ph 101) 1:1 Lactose monohydrate 1:1 Binder Polyvinylpyrrolidone (Kollidon 30) 1:1 Cross-linked Polyvinylpyrrolidone (Crospovidone) 1:1 Hydroxypropylmethylcellulose (HPMC 5 cps) 1:1 Disintegrant Croscarmellose Sodium (Ac-Di-Sol) 1:1 Sodium Starch Glycolate (Explotab) 1:1 Lubricant Magnesium Stearate 1:1 Glidant Colloidal Silicon Dioxide (Aerosil) 1:1

2 Shamama Javed et al. / Journal of Pharmacy Research 2012,5(3), 2.3 Sample preparation for ph stability studies The effect of ph on the stability of silybin in buffered aqueous silymarin solution was studied in this experiment and a complete ph-rate profile was obtained to identify the ph of maximum stability for silybin: the analytical marker of silymarin complex (70% standardized extract). Aqueous buffers as mentioned below were used to produce solutions over a wide range of ph. A stock solution of silymarin (100µg/ml) was prepared by dissolving 10 mg of silymarin in 100 ml methanol. To 10 ml of methanolic stock solution of silymarin, 10 ml of buffer (ph 1.0, 3.0, 5.0, 7.0, 9.0) was added and mixture was analyzed for stability by RP HPLC-UV up to 3 h using methanol and water (1% acetic acid) as the mobile phase in the ratio 50: 50, flow rate 1ml/min, injection volume 20 µl and wavelength at 288nm. The silybin level was analyzed to evaluate the impact of ph on its stability. The rate constant (K) for each ph was calculated from the plot of Log (% drug remaining) i.e. Log C versus Time. Finally Log K versus ph was also plotted. The minimum of this curve is the ph of maximum stability of silybin. [6] List of buffers: a) 0.1N HCl ph 1.0: Place 25 ml of the 0.2 M KCl in a 100 ml volumetric flask, add 42.5 ml of 0.2 M HCl and then add water to make volume upto 100 ml. b) Potassium hydrogen phthalate ph 3: Place 50 ml of 0.1 M potassium hydrogen phthalate in a 100 ml volumetric flask and add 22.3 ml of 0.1M HCl and add water to make volume upto 100 ml. c) Acetate Buffer ph 5.0: Place 2.86 ml of glacial acetic acid and 1ml of 50% w/v solution of NaOH in 100 ml volumetric flask, add water to make volume upto 100 ml. d) Phosphate buffer ph 7.0: Place 25 ml of 0.2 M KH 2 PO 4 in 100 ml volumetric flask, and add 19.0 ml of 0.2 M NaOH and add water to make volume upto 100 ml. e) Borate buffer ph 9.0: Place 25 ml of 0.2 M boric acid and KCl in a 100 ml volumetric flask, add 21.9 ml of 0.2 M NaOH and add water to make volume upto 100 ml. 2.4 Sample preparation for solubilization studies by UV spectroscopy The solubility studies were performed on a UV-Visible double beam spectrophotometer (Shimadzu, Japan). The methodology and data were validated for linearity, accuracy, precision in the drug concentration range of 2-20µg/ml. The saturation solubility of silymarin (70% standardized extract) was determined in the following: double distilled water, 0.1N HCl, ph 4.5 acetate buffer, ph 6.8 phosphate buffer, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0, 2% (w/v) in SLS in water and 1.0% and 2.0% polysorbate 80. Excess silymarin was added to 4 ml of the solvent in a glass vial and agitated continuously at 37 ± 1ºC in a thermostated shaking water bath (Scientific Systems) for 48 h. The contents were then filtered through 0.22 µm filter and the filtrate was analyzed spectrophotometrically at 288 nm (λ max ) after appropriate dilutions with the respective solvent. The calibration plots in UV were developed, saturation solubility in all the mentioned solvents was assessed and micellar solubilization equilibrium coefficients (k*) of SLS was also determined. 3. RESULTS AND DISCUSSION 3.1 DSC Studies Interactions in the samples are derived from DSC by changes in the thermal events, such as elimination of an endotherm or exotherm peak, or appearance of a new peak. However, some broadening of peaks leading to changes in the area, onset of peak, and changes in peak temperature occur simply due to mixing of the components without indicating any significant interaction. If all the thermal features more or less remain the same, the compatibility can be expected. [7] In this study the excipients were grouped according to their interactions with silymarin into compatible, slightly interacting and completely incompatible. Silymarin (70% standardized extract) is a multi-component drug that does not possess typical crystallinity which gives indicative peaks in curves of DSC. Many peaks were observed in the pure silymarin thermogram mainly, a broad endothermic event between 50ºC and 120ºC. This peak corresponds to melting peak of silybin, an active constituent of silymarin complex [Fig. 1a]. The thermal behavior showed above 200ºC in the thermogram is typical of a decomposition process of organic compounds. Zhang et al., 2007 reported in their findings the melting peak of silybin at 164ºC. The difference can be attributed to different sample geometry. [8] The excipient Ac-Di-Sol exhibits a shallow broad endotherm as its characteristic feature [Fig. 1b]. This might be due to volatilization of absorbed water, since it is reported in literature that the thermal analysis of cellulose showed endotherms above 100ºC that were attributed to water vapor. Therefore, combination of silymarin with Ac-Di-Sol exhibits the characteristic peak of silymarin and Ac-Di-Sol indicating compatibility between the two components. Some changes in peak shape and height to- width ratio can be seen because of possible differences in mixture sample geometry. [9] The silymarin- Explotab mixture showed the combined features characteristic of silymarin and Explotab [Fig. 1c]. When two substances are mixed, the purity of each may be reduced leading to slightly lower melting endotherms and slight shift in peaks. [10] In this case a lower silymarin endotherm Figure 1 (contd.). DSC thermogram of silymarin with various tablet excipients. Figure 1: DSC thermograms of silymarin with various tablet excipients.

3 Shamama Javed et al. / Journal of Pharmacy Research 2012,5(3), is seen and melting peak of Explotab is observed from 180ºC- 280ºC. As such no interaction was found between the two components, thus indicating compatibility. 200ºC showed the melting point of SLS (which is between ºC). No interaction between the two was observed, indicating compatibility [Fig. 1g]. Polyvinylpyrrolidone (Kollidon 30) is a water-soluble polymer, widely used as binder in tabletting process. The DSC thermogram of silymarin and Kollidon 30 demonstrated no thermal transition of Kollidon 30 in temperature range under study and drug characteristic endothermic event was clearly observed indicating compatibility between them [Fig. 1d]. Similar case was observed with HPMC, indicating compatibility between drug and HPMC [Fig. 1e]. Magnesium stearate is used as lubricant to prevent sticking, to improve the flow properties of the mixture and reducing the attrition during compression. The thermogram of silymarin and magnesium stearate presented the drug endothermic peak and a shoulder peak from ºC which is characteristic melting peak of magnesium stearate followed by a sharp peak at 200 ºC due to the melting of magnesium palmitate (often present as impurity in commercial lots of magnesium stearate). Similar findings were observed by Bruni et al., [10] Thus mixture was found to be compatible with each other during the study [Fig. 1f]. In the silymarin sodium lauryl sulphate mixture, the characteristic endotherm of silymarin can be seen as well as another endothermic peak nearly at With Methocel, the thermogram showed silymarin characteristic feature and an endotherm of dehydration at 120 ºC, which is characteristic of Methocel [Fig. 1h]. This endotherm is present on the thermogram of cellulosic materials due to the interaction of the water and the non-substituted hydroxyl groups of the cellulose derivatives [11]. It does indicated little incompatibility between silymarin and methocel by an interaction upon heating and this may not happen on storage at room temperature. Polyvinylpolypyrrolidone (Crospovidone) is a highly cross-linked modification of PVP. Here shortening of drug characteristic endotherm was observed with crospovidone indicating a strong solid-solid interaction upon heating [Fig. 1i]. It does indicate incompatibility between drug and crospovidone either by dissolution of drug in crospovidone or an interaction upon heating. Interesting findings were observed in case of silymarin starch and MCC ph 101 mixtures. The splitting/shouldering of drug characteristic peak was observed greatly with both the excipients and the excipient characteristic features remained the same. A broad endotherm characteristic feature of MCC ph 101 [Fig. 1j] and melting/decomposition of starch at 250ºC [Fig. Figure 2. FT-IR spectrum of silymarin-excipient mixtures. Figure 2 (contd.). FT-IR spectrum of silymarin-excipient mixtures

4 Shamama Javed et al. / Journal of Pharmacy Research 2012,5(3), 1l] were evident. It was finally hypothesized that some interactions could be possible at elevated temperature during the DSC studies, or it could be attributed to the interaction with the impurities which are likely to be present in the case of starch and MCC ph 101 as both are obtained from natural sources. [7] 2000 cm -1 were significantly affected by interactions with some excipients and their interpretation became the center point of our study. Therefore, the spectrum provided in the fingerprint region of silymarin i.e. from 2000 cm cm -1 in all the silymarin-excipient mixtures plays a vital role in understanding the interactions. The silymarin-lactose thermogram confirmed the stability of silymarin with lactose monohydrate as the drug characteristic peak and lactose characteristic peak were distinguished [Fig. 1k]. The colloidal silicon dioxide is widely used in pharmaceutical products. It provides desirable flow characteristics to powders in tablet making processes. The thermal behavior of silymarin and colloidal silicon dioxide showed strong solid-solid interaction with complete disappearance of drug characteristic peak, indicating incompatibility between the two [Fig. 1m]. One cannot conclusively state that this incompatibility will be encountered on storage at room temperature. 3.2 FT-IR Studies IR spectroscopy is one of the most powerful analytical techniques which offer the possibility of chemical identification of organic compounds easily. The technique is based upon the simple fact that a chemical substance shows marked selective absorption in the infrared region. Depending upon the types of bonds present in a molecule, various wavelengths are found to be absorbed in the infrared spectrum of the molecule giving rise to absorption bands. Infrared spectrum can be divided into two regions for the purpose of interpretation: a)absorption bands from 4000 to 1250 cm -1 is characteristic of the type of bonds present. b)absorption bands less then 1250 cm -1 are associated with complex vibrational and rotational energy changes of the molecule as a whole. This region is, therefore, very useful for establishing the identity of a compound and is sometimes referred to as the fingerprint region. Fingerprint region can be subdivided into three regions as follows: cm -1, cm -1, below 1000 cm -1. [12] According to FT-IR spectrum presented by M.S. El-Samaligy et al., 2006, the drug characteristics peaks were marked at cm -1, cm -1 and cm -1 as shown in [Fig. 2a]. Whereas, Leko, 2008 discussed the IR spectrum of silymarin as having a characteristic stretching band of alcoholic and phenol O-H bonds at 3400 cm -1, and ketone stretching band at about 1640 cm -1. Apart from these other prominent bands were 1745, 1513, 1465, 1358, 1275, 1160, 1083, 1027, 992, 813, 782, 644 cm -1. [13] Throughout our study it was observed that the drug characteristic band at 3400 cm -1 remained unaffected in all drug-excipient mixtures compatibility testing because of its much prominent nature. Whereas drug bands below ph Linear Equation R 2 K Log K T 1/2 (days) 1 y= x y= x y= x y= x y= x Figure 4. Log K vs ph profile of silybin In our study the FT-IR spectrum of pure drug silymarin (70% standardized extract) in the fingerprint region showed the characteristics bands at 1640, 1512, 1465, 1362, 1275, 1160, 1083, 1030, 995, 821, 781 and 645 cm -1 [Fig. 2b]. These were concordant to those mentioned above confirming the au- Table 3: The Linear equation, regression coefficients, observed first order rate constant and t1/2 for silybin degradation in buffered aqueous silymarin solution. thenticity of our drug sample. Infrared studies revealed that major drug characteristic bands were present in all spectra while no new band or major shift in characteristic peak occurred during the interaction study with lactose monohydrate, croscarmellose sodium, HPMC, MCC ph 101, magnesium stearate, PVP k30, crospovidone and sodium starch glycolate (Fig. 2c 2j) except in the case of colloidal silicon dioxide (Fig. 2k). The samples mixed with silicon dioxide in 1:1 mixture showed the complete change in drug fingerprint region. This may be attributed to the interaction between the two components. Therefore, the use of aerosil as an excipient should be avoided in formulations containing silymarin since it may act as a catalyst in the thermal decomposition of this drug even though it is employed in very low concentrations (usually 1% of the total tablet weight). Table 4: The calibration plot linear equation, R 2 and slope values of silymarin in various vehicles Vehicle Linear equation R 2 Slope Figure 3. Log C vs time (min) curve of silybin in aqueous buffered silymarin solutions Double distilled water Y=0.014x % SLS in D.D. water Y=0.033x % SLS in D.D. water Y=0.076x % SLS in D.D. water Y=0.056x % SLS in D.D. water Y=0.052x % SLS in D.D. water Y=0.049x % SLS in D.D. water Y=0.067x % SLS in D.D. water Y=0.055x % SLS in D.D. water Y=0.064x % Tween 80 in D.D water Y=0.016x % Tween 80 in D.D water Y=0.035x N HCl (ph 1.2) Y=0.032x Acetate buffer (ph 4.5) Y=0.043x Phosphate buffer (ph 6.8) Y=0.033x D.D Double distilled; and SLS is sodium lauryl sulphate

5 Shamama Javed et al. / Journal of Pharmacy Research 2012,5(3), Table 5: Saturation solubility of silymarin in different vehicles (n=3). Solvents Solubility Solubility enhancement factor (s) µg/ml (Mean ± SD) s (S medium /S water ) Double distilled water 50 ± % SLS in D.D. water 1160 ± % SLS in D.D. water 1600 ± % SLS in D.D. water 2030 ± % SLS in D.D. water 2680 ± % SLS in D.D. water 3890 ± % SLS in D.D. water 4190 ± % SLS in D.D. water 5530 ± % SLS in D.D. water 6124 ± % Tween 80 in D.D 1560 ± % Tween 80 in D.D 2605 ± N HCl (ph 1.2) 800 ± Acetate buffer (ph 4.5) 930 ± Phosphate buffer (ph 6.8) 1045 ± D.D Double distilled; and SLS is sodium lauryl sulphate. 3.4 Solubility studies by UV Spectroscopy Solubility is an important physical parameter that affects its absorption and bioavailability; therefore it is an important preformulation study. The calibration plots of silymarin were made in various vehicles [Table 4] and from there solubility of silymarin was determined [Table 5]. The aqueous Table 6: The micellar solubilization equilibrium coefficients (k*) of SLS Molar Solution of SLS Equilibrium Coefficient (L/mol) 0.1% ( M) 7730± % ( M) 4610± % ( M) 4000 ± % ( M) 4126± % ( M) 4052± % ( M) 3217± % (0.034M) 3235± % (0.069M) 1768±116 solubility of silymarin (double distilled water) was found to be 50µg/ml (0.05± 0.10 mg/ml) at 37 ºC, according to the method described above. Therefore, silymarin can be considered as a practically insoluble drug and the findings were concordant with Li and Hu [14] The solubility of silymarin in various ph buffers increased considerably as compared to double distilled water and the ph-solubility curve is shown in Figure 5. Figure 5: Solubility enhancement factor (s) at 37ºC as a function of concentration of surfactant (% SLS in water). 3.3 ph stability studies by RP HPLC-UV The effect of ph on the degradation kinetics of silybin in silymarin solution The degradation of silybin in buffered aqueous silymarin solution appears to fit in a first order reaction. The Log C vs Time (min) for the ph range of 1,3,5,7 and 9 is shown in Figure 3. The Linear equation, R 2, rate constant (k), Log K and t 1/2 are summarized in Table 3. The silybin content of silymarin complex was found to be stable in ph range of 1-7 whereas degradation was observed at ph 9. The Log K plotted against ph values is shown in Figure 4. solubility in mcg/ml ph Figure 6. ph solubility profile of silymarin. On the other hand, there were reasonably increased solubilities when silymarin were mixed into aqueous solutions of surfactants, such as sodium lauryl sulphate and polysorbate-80. In the gut, the presence of bile salts, lecithins, and other lipids can increase the solubility of poorly water soluble drugs. Therefore, outside human body pharmaceutical surfactants and emulsifiers are effective solubilizers. It is known that the enhancement of solubilization using surfactants can be upto 140 fold compared with simple aqueous solution. [15] The addition of different concentrations of SLS significantly increased the solubility of silymarin. The highest solubility enhancement of folds was achieved in this experiment using 2.0% SLS whereas, 2.0 % Tween 80 showed only a 52.1 fold enhancement [Figure 6], indicating that the incorporation of silymarin into SLS micelle was significant. The equilibrium coefficient, k, was determined by fitting the data to the following equation: s (S medium /S water ) = 1+ k* C m(sls). Where s = solubility enhancement factor and C m(sls) is the molar concentration of SLS. Results are shown in Table CONCLUSIONS In this study the DSC confirmed that lactose monohydrate, Ac-Di-Sol, Explotab, Kollidon 30, magnesium stearate, hydroxypropyl methylcellulose and sodium lauryl sulphate were compatible with the silymarin. Occurrence of strong solid-solid interaction upon heating was observed with Crospovidone, Methocel and Aerosil. Splitting of the drug peak was observed with silymarin-starch and silymarin-mcc ph 101 due to the interaction of silymarin with the impurities which are likely present in MCC and starch, both obtained from natural source, whereas, FT-IR confirmed the incompatibility between silymarin and Aerosil only. Thus DSC and FT- IR can be employed for the evaluation of solid state interactions as an aid to excipient selection. The solution state ph stability studies of silybin in aqueous buffered silymarin solution showed stability in ph range 1-7 and major degradation at ph 9. The solubility studies confirmed the sodium lauryl sulphate as a better solubilizer of silymarin by increasing the solubility of silymarin upto folds as compared to solubility in plain water. These studies can aid in better formulation development for silymarin. ACKNOWLEDGEMENTS S. Javed wishes to thank the Indian Council of Medical Research (ICMR), New Delhi, India, for providing financial assistance in the form of Senior Research Fellowship (SRF). The authors are also thankful to the Maneesh Pharmaceuticals Ltd. Mumbai, India, for providing the gift sample of silymarin and Arbro Pharmaceuticals Ltd. Kirti Nagar, New Delhi, India, for providing the different instrument facility.

6 Shamama Javed et al. / Journal of Pharmacy Research 2012,5(3), Conflict of Interest: Authors declare no conflict of interest. REFERENCES 1. Book chapter Antipas AS and Landis MS. Solid state excipient compatibility testing. In: Baertschi SW, editor. Pharmaceutical stress testing: Predicting drug degradation. Taylor & Francis, pp Bruni G, Amici L, Berbenni V, Marini A and Orlandi A. Drug- Excipient compatibility studies: Search of interaction indicators. J Therm Anal Calorim. 2002; 68: Differential Scanning Calorimetry. Differential_scanning_calorimetry. 4. Javed S, Kohli K, Ali M. Patented bioavailability enhancement techniques of silymarin. Recent Pat Drug Deliv Formul. 2010; 4: Van Dooren AA and Duphar BV. Design for Drug-Excipient Interaction Studies. Drug Dev Ind Pharm. 1983; 9: Jin P, Madieh S, Augsburger LL. The solution and solid state stability and excipient compatibility of parthenolide in fewerfew. AAPS PharmSciTech. 2007; 8: E1-E6. 7. Joshi BV, Patil VB, Pokharkar VB. Compatibility studies between carbamazepine and tablet excipients using thermal and non-thermal methods. Drug Dev Ind Pharm. 2002;28: Zhang JQ, Liu J, Li XL and Jasti BR. Preparation and characterization of solid lipid nanoparticles containing silibinin. Drug Deliv. 2007; 14: Botha SA, Lotter AP. Compatibility study between naproxen and tablet excipients using differential scanning calorimetry. Drug Dev Ind Pharm. 1990;16: Bruni G, Berbenni V, Milanese C, Girella A, Marini A. Drugexcipient compatibility studies in binary and ternary mixtures by physico-chemical techniques, J Therm Anal Calorim. 2009; doi: /s z 11. Viera RGP, Filho GR, De Assuncao RMN, Meireles CS, Vieira JG, De Oliveira GS. Synthesis and characterization of methyl cellulose from sugar cane bagasse cellulose, Carbohyd Polym. 2007; 67: Book, authored Chatwal GR, Anand SK. Instrumental methods of chemical analysis. Himalaya Publishing House; Vladimir L. Method for isolation of silymarin from Silybum marianum seeds.us B2, Li F-Q, Hu J-H. Improvement of the dissolution rate of silymarin by means of solid dispersions. Chem Pharm Bull. 2004;52: Book chapter Lobenberg R, Amidon GL, Vieira M. Solubility as a limiting factor to drug absorption. In: Jennifer BD, Lennermas H, editors. Oral drug absorption prediction and assessment. Marcel Dekker, Inc., New York; p Source of support: ICMR,New Delhi; Conflict of interest: None Declared