Preparation, Physicochemical Characterization, Dissolution and Formulation Studies of Telmisartan Cyclodextrin Inclusion Complexes

 

Rajesh Kane^1,*, Suresh Naik¹, Shrinivas Bumrela¹ and Bhanudas Kuchekar²

¹Sinhgad Institute of Pharmaceutical Sciences, Lonavala. Dist-Pune. Maharashtra, India. 410- 401

²MIT’s Maharashtra Institute of Pharmacy, Erandavane, Pune. Maharashtra, India.

*Corresponding Author E-mail:    rnkane2005@rediffmail.com  

ABSTRACT:

The objective of this research was to prepare, characterize and to study dissolution properties of inclusion complexes of telmisartan (TLM), with β- cyclodextrin and hydroxypropyl- β- cyclodextrin and to study its effect on rate of dissolution. The phase solubility curve was classified as an A_P type for both the CD’s, which indicated formation of inclusion complex of TLM in 1:2 stoichiometries with β-CD and HP-β-CD.

 

The inclusion complexes in molar ratio of 1:2 were prepared by various methods such as kneading, co-evaporation and physical mixing. The molecular behavior of TLM in all samples were characterized by fourier- transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder x-ray diffraction studies.

 

The result of studies showed inclusion of TLM molecule into cyclodextrin cavities. The highest improvement in in-vitro dissolution of TLM was observed in complex prepared with HPβ-CD using kneading method. Mean dissolution time (MDT) and similarity factor (f2) indicated significant difference between the release profile of TLM from complexes, physical mixture and pure TLM.

 

The highest improvement in solubility and in-vitro drug release were observed in inclusion complex prepared with HPβ-CD by kneading method. Improvement in solubility and in-vitro drug release of Telmisartan were more with HPβ-CD as compared to β-CD

 

 

 

INTRODUCTION:

Telmisartan (TLM) :  (4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid; Figure 1) is an orally active  direct-acting AII, AT₁receptor antagonist and  possess therapeutic potential in the pharmacotherapy of hypertension¹. It is a white crystalline powder having molecular formula C₃₃H₃₀N₄O₂ , molecular weight of 514.6 and a melting point of 261 to 263°C². The results have established that telmisartan exerts potent and sustained antagonism of AII-mediated pressor responses in vivo, and effectively lowers blood pressure in animal models of hypertension as well as in humans. The hypotensive effects are of long duration and having potential superiority over other similar type of drugs like losartan³. 

 

In addition to blocking the Renin-Angiotensin System (RAS), telmisartan acts as a selective modulator of Peroxisome proliferator-activated receptor gamma (PPAR-γ), a central regulator of insulin and glucose metabolism. It is believed that telmisartan’s dual mode of action may provide protective benefits against the vascular and renal damage caused by diabetes and cardiovascular disease (CVD) ⁴.

 

Telmisartan is soluble in DMSO >5 mg/mL at 60 °C, slightly soluble in alcohol and methylene chloride and practically insoluble in water. The solubility of telmisartan in aqueous solutions is strongly pH-dependent; it is poorly soluble in the pH range of 3–9 with maximum solubility observed at high and low pH ⁵. Due to its hydrophobic nature (octanol/water partition coefficient 3.2 at pH of 7.4) TLM shows low dissolution profile in gastrointestinal fluid resulting poor absorption, distribution and consequently poor target organ delivery ⁶. Improvement of aqueous solubility in such cases shall lead to improved therapeutic efficacy of the drug.

 

Cyclodextrins (CD’s) with their cylinder-shaped cavities capable to form inclusion complexes with a wide range of commonly used drugs by taking the whole molecule or part of it into the cavity and known to improve the aqueous solubility of drugs. Many drugs such as valsartan, Lovastatin , Praziquantel ^7-9,etc have been complexed with CD’s and formulated for enhancing solubility and therapeutic activity.

 

β-cyclodextrin and its more hydrophilic derivative hydroxypropyl-β-cyclodextrin (HP-β-CD) have been selected for the complexation study of telmisartan. In the present study inclusion complexes of TLM with β-CD and HP-β-CD were prepared by kneading, co-evaporation and physical mixing and characterized by Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) with the aim of improving the aqueous solubility and dissolution profile of the TLM.

 

Fig 1: Structural formula of Telmisartan

 

MATERIALS:

HP-β-CD (Mole. Wt.1500) and β-CD (Mole. Wt. 1135) were generous gift from Gangwal Chemicals Pvt. Ltd. Mumbai. India. Telmisartan was received as a gift sample from Unichem Laboratories, Raigad Maharashtra. Lactose monohydrate, microcrystalline cellulose, povidone, silicone dioxide, and magnesium stearate were purchased. All chemicals and solvents used in this study were of A.R. grade. Freshly prepared double distilled water was used throughout the work.

 

METHODS:

Phase solubility study:

Phase-solubility studies were performed by the method of Higuchi and Connors ¹⁰. TLM, in constant amounts (5 mg) that exceeded its solubility, was transferred to screw capped vials containing 15 ml of aqueous solution of β-CD or HPβ-CD at various molar concentrations (0, 3.0, 6.0, 9.0, 12.0, and 15.0 mM). The contents were stirred on rotary shaker (Remi, India) for 72 h at 37 ⁰C ± 0.1 ⁰C and 300 rpm. The time duration was fixed based on pilot experiment and found to be sufficient to achieve equilibrium of mixture.

 

After reaching equilibrium, samples were filtered through a 0.22 µm membrane filter, suitably diluted and analyzed spectrophotometrically for drug content at 297 nm (Jasco-V 530, UV/Visible spectrophotometer, Jasco Inc., Japan). Solubility studies were performed in triplicate.

 

Preparation of inclusion complexes:

Telmisartan and CD’s were sieved through 120 # prior to their use. Complexes of TLM with β-CD and HP-β-CD were prepared in the molar ratio of 1:2 by different methods mentioned below. For better identification, the samples are designated with different abbreviations in table 1.

 

Table 1. Abbreviations used to designate different samples

Type of CD’s	Method of preparation	Abbreviation used
β –CD	Physical mixture	PMB
β -CD	Co-evaporation	COB
β -CD	Kneading	KNB
HP β –CD	Physical mixture	PMH
HP β –CD	Coevaporation	COH
HP β –CD	Kneading	KNH

 

Physical mixture:

Physical mixture (PM) of CD’s and TLM were prepared by simply mixing powders with a spatula in 1:2 molar ratios for 15 min and then sieved through 120 #.

 

Co-evaporation method:

For preparation of complexes by co evaporation method TLM and CD’s were mixed in 1:2 molar ratio, 10 ml of methanolic solution of TLM was added slowly to 10 ml of the aqueous solution of CD followed by stirring at 1000 rpm using magnetic stirrer at 37⁰c for 24 hrs. The solvents were then evaporated at 45-50 ⁰C. The resultant solids were pulverized and then sieved through 120 #.

 

Kneading method:

For preparation of complexes by kneading method, the TLM and CD’s were taken in 1:2 molar ratios. The CD was triturated in a mortar with small quantity of water to obtain a homogeneous paste. TLM was then added slowly while grinding; a small quantity of methanol was added to facilitate the dissolution of TLM. The mixtures were then grounded for 6 hrs. During this process, an appropriate quantity of water was added to the mixture to maintain a desired consistency. The pastes were dried in an oven at 45-50 ⁰C for 24 hrs. The dried complexes were pulverized and then sieved through 120 #.

 

Determination of Drug content in complexes:

The samples of complexes and physical mixtures were assayed for TLM content by dissolving a fixed amount of the complexes in methanol and analyzing for the TLM content spectrophotometrically at 297 nm.

 

Characterization of complexes:

Fourier transform infrared (FTIR) spectroscopic analysis:

FTIR spectra of moisture free powdered samples of TLM, CD’s, its PM’s and complexes with β-CD and HP-β–CD were taken using a FTIR spectrometer (Jasco FTIR 4100, Japan) by mixing with potassium bromide.

 

Powder X-ray diffraction (PXRD) analysis:

Powder X-ray diffraction patterns of all samples were determined using Powder X-ray diffractometer (Bruker AXS Advance^TM Germany), at a scan rate of 1⁰ min^–1 from 2θ range from 5⁰ to 50⁰.

Differential scanning calorimetry (DSC) analysis:

DSC scans of all powdered samples were recorded using Shimadzu DSC 60. The samples (1 mg) were analyzed at a scanning rate of 10 ⁰C /min, over the temperature range of 30 ⁰C to 300 ⁰C.

 

 

Dissolution Studies:

Dissolution studies of TLM in powder form, its PM’s and complexes with β-CD and HP-β-CD were performed to evaluate drug release profile. Dissolution studies were performed on USP dissolution apparatus type II with 900 ml dissolution medium Phosphate buffer (pH 7.5) at 37 ⁰C ± 0.5 ⁰C at 75 rpm for 45 min. At fixed time intervals 5 ml aliquots were withdrawn, filtered, suitably diluted and assayed for TLM content by measuring the absorbance at 297 nm. (Pilot experimental data indicated no change in the λ _max of TLM due to the presence of CD’s in the dissolution medium.) Equal volumes of fresh medium (pre-warmed to 37 ⁰C) were replaced into the dissolution medium to maintain constant volume throughout the test period. Dissolution studies were performed in 6 replicates, and calculated mean values of cumulative drug release were used while plotting the release curves.

 

Formulation studies:

Tablets containing 40 mg of TLM were prepared by direct compression using different excipients like Lactose monohydrate, colloidal silicon dioxide, and magnesium stearate. Tablets containing complexes (equivalent to 40 mg TLM) prepared by kneading and co-evaporation method were also prepared similarly using less quantity of lactose. The blend was compressed on a six-station single rotary machine (Jaguar, India) using oval-shaped, punches to obtain tablets having length 16 mm, width 7 mm, thickness 4.5 mm and hardness 3–5 kg/cm². The tablets were studied in 6 replicates for release profile of TLM using the same method described in dissolution studies.

 

Statistical analysis:

Model independent mathematical approach proposed by Moore and Flanner¹¹ for calculating a similarity factor f₂ was used for comparison between dissolution profiles of different samples. It also has been adopted by the US Food and Drug Administration's Center for Drug Evaluation and Research ¹² and by the Human Medicines Evaluation Unit of the European Medicines Agency ¹³ as a criterion for assessing the similarity of two dissolution profiles ^{14, 15}. The similarity factor (f₂) is a measure of similarity in the percentage dissolution between two dissolution curves and is defined by following equation:

 

..1

 

Where, n is the number of withdrawal points, Rt is the percentage dissolved of reference at the time point, t and Tt is the percentage dissolved of test at the time point t. A value of 100% for the similarity factor (f₂) suggests that the test and reference profiles are identical. Values between 50 and 100 indicate that the dissolution profiles are similar whilst smaller values imply an increase in dissimilarity between release profiles. In order to understand extent of improvement in dissolution rate of TLM from its complexes and physical mixture, the obtained dissolution data of pure TLM, it’s PM and complexes with CD’s were fitted into equation

…….2

 

Here, i is dissolution sample number, n is number of dissolution times, t _mid is time at the midpoint between times t_i and t_i-1, and ΔM is the amount of TLM dissolved (µg) between times t_i and t_i-1. MDT reflects the time for the drug to dissolve and is the first statistical moment for the cumulative dissolution process that provides an accurate drug release rate. It is accurate expression for drug release rate. A higher MDT value indicates greater drug retarding ability ^{16, 17}.

 

RESULTS AND DISCUSSION:

Phase solubility:

Phase solubility analysis is among the preliminary requirements for optimization of the development into inclusion complexes of the drugs which can be used for evaluation of the affinity between CD’s and drug molecule in water. Albeit CD’s are known to generate aggregates (self-associates) in aqueous solvents ^18-20 the method is widely used for the determination of the molar ratios in drugs-CD complexes with CD’s. The phase solubility curve of TLM showed a linear increase in solubility of TLM with an increase in concentrations of CD’s in water (Figure 2.). Solubility of TLM is increased by 9.93 fold and 25.49 fold at 37 ⁰C at 15 mM concentrations of β-CD and HP-β-CD, respectively. The Gibbs free energy of transfer (ΔG_tr⁰) of TLM from pure water to aqueous solutions of CD’s was calculated using the values from phase solubility curve (Figure 2) and applying the equation mentioned below.

 

 

………..3

 

Where, S₀/S_s = the ratio of molar solubility of TLM in aqueous solution of CD’s to that of the pure water ²¹. The obtained values of ΔG_tr⁰ are shown in table 2. In the present experiment ΔG_tr⁰ values were all negative for CD’s at various concentrations, suggesting the spontaneous nature of TLM solubilization. These values further indicate greater degree of solubility improvement with HP-β-CD as compared to β-CD. The phase solubility plot showed an A_P type solubility curve for both the CD’s, which indicated formation of inclusion complex of TLM in 1:2 stoichimetric ratios with β-CD and HPβ-CD. The stability constants (Ks) for the complexes at 37 ⁰C, assuming a 1:2 stoichiometry, calculated from the slope of preliminary straight line portion of the phase solubility curve were 699.844 M^–1 for β-CD: TLM and 2389.93 M^–1 for HP-β-CD:TLM, which indicated stable complex formation. Since Ks of HP-β-CD: TLM and β-CD: TLM in the range of 200–5000 M^–1 there is an increase in the dissolution profile which would certainly increase bioavailability of TLM.

 

Table 2. Gibbs free energy of transfer (ΔG_tr⁰) for solubilization process of  Telmisartan in aqueous solutions of cyclodextrins at 37 ⁰C

 

 

 

Fig 2: Phase solubility curve of Telmisartan in aqueous solution of β-CD and HPβ- CD at 37 ⁰C

 

 

Drug content:

The drug content of the PMB, PMH, COB, COH, KNB and KNH were found to be 95.98% (±4.48), 95.44% (±5.03), 96.74% (±3.54), 97.16% (±3.15), 96.81% (±3.6), and 97.82% (±2.76), respectively.

 

Characterization of complexes:

Fourier transform Infrared (FT-IR) Spectroscopic analysis:

The FT-IR spectra of PMB, KNB, COB, PMH, KNH and COH were compared with spectra of β-CD, HPβ-CD and TLM (Figure 3). The spectrum of pure TLM depicts the characteristic peaks at 3059 cm^–1 (Aromatic C–H stretch), 2957, cm^–1 (Aliphatic C-H stretch)  , 1697 cm^–1 (- COOH acid), 1599 cm^–1  (Aromatic C=C Bend and Stretch), 1459 cm^–1 (C–H bend), 1382 cm^–1 (-OH bending and -C=O stretching of –COOH acid) 741 and 756 cm^–1 (ring vibration due to 1,2-disubstituted benzene), respectively.

 

The FT-IR spectra of β-CD and HP-β-CD are characterized by intense bands at 3300–3500 cm^–1due to O–H stretching vibrations. The vibration of the –CH and CH₂ groups appears in the 2800–3000 cm^–1 region. The presence or absence of characteristic peaks associated with specific structural groups of the drug molecule was noted. The chemical interaction has been reflected by changes in the characteristic peaks of TLM, depending on the degree of interaction. The FT-IR spectra of PMB, KNB, COB, PMH, KNH and COH showed shift in peaks than those of CD’s and TLM indicating chemical interaction between CD’s and TLM during coevaporation, kneading, and physical mixing. The FT-IR spectra showed the absence of the characteristic peak of TLM at 1697.05 cm^–1 (- COOH acid), 2957.30 cm^–1  (aliphatic C-H stretch), 1382.71 cm–1(-OH bending and -C=O stretching of –COOH acid), 741 and 756 cm^–1 (ring vibration due to 1,2-disubstituted benzene) in complexes, indicating inclusion of TLM in CD’s cavity in them.  Hence it could be presumed the formation of inclusion of 1, 2-disubstituted benzene ring and carboxylic acid group of TLM in the cyclodextrin complexes.

 

Fig 3: FT IR Spectra of Telmisartan, CD’s and its complexes (a) TLM, (b) β -CD, (c) PMB, (d) COB, (e)KNB, (f) HP β –CD, (g) PMH, (h) COH, (i) KNH

 

Powder X-ray diffraction (PXRD) analysis:

Powder X-ray diffraction spectroscopy (PXRD) has been used to assess the degree of crystallinity of the given sample. When complexes of drug and CD’s are formed, there was increase in amorphousness and consequently solubility of drug. The PXRD spectra’s of all the samples are shown in Figure 4. Telmisartan spectra depicts major peak at 2θ values of 6.8, 9.7, 14.23, 14.2, 15.1, 16.2, 18.3, 20.7, 22.3, and 25.1, while β-cyclodextrin spectra showed major peaks at 2θ values of 5.07, 8.87, 9.65, 11.87, 13.61, 17.16, 19.83, 21.06,  26.76 and 29.93. Due to amorphous nature of HPβ-CD, no major peaks were detected in its spectra. Degree of crystallinity was decreased to maximum extent in case of complexes prepared using HPβ-CD and β-CD. Hence, from present structural data of complexes, it can be confirmed that inclusion of TLM in CD’s cavity has been occurred.

 

Fig 4: PXRD Spectra of Telmisartan, CD’s and its complexes (a) TLM, (b) β -CD, (c) PMB, (d) COB, (e)KNB, (f) HP β –CD, (g) PMH, (h) COH, (i) KNH

 

Differential scanning calorimetry (DSC) analysis:

Differential scanning calorimetry analysis has largely been used to detect all processes in which energy is required or produced. The thermograms of all samples are presented in Figure 5. The TLM showed a melting peak at 265.45–268.82 ⁰C. In the thermogram of the β-CD and HPβ-CD peak between 75 ⁰C –125 ⁰C was due to loss of water from CD’s molecules. In the thermogram of all samples, peaks due to β-CD and HPβ-CD were observed at the same position i.e. between 75 –125 ⁰C. Peak of TLM at 265–268 ⁰C was present at the same position i.e. near to 265 ⁰C in PMB, COB, PMH, and KNB. In case of KNH and COH, intensity of TLM peak is very less this may be attributed to trapping of TLM in the CD’s cavity. This further confirms that kneading method is the best method for the preparation of inclusion complexes.

 

Dissolution studies:

The dissolution studies were carried out with TLM and its complexes and physical mixture using dissolution medium phosphate buffer pH 7.5. DP₃₀ min (percent drug dissolved within 30 min), time to dissolve 50% drug (t₅₀%) and mean dissolution time (MDT) are reported in table 3. The data revealed the onset of dissolution of pure TLM was very low (51.27 % within 30 min). COH, KNH, COB, and KNB significantly enhanced dissolution rates within 30 min as compared to pure TLM, PMB and PMH; see Figure 6. It is evident that the dissolution rate of pure TLM is very low (60.34 % in 45 min.). Inclusion complexes KNB, COB, KNH and COH significantly enhanced dissolution rate of TLM (75–81% within 45 min). The likely factors responsible for the improvement in dissolution rates of complexes and PM’s are, reduction of crystal size, solubilization effect of carrier, improved wettability etc (22). MDT of TLM was 12.45 min in dissolution medium. The MDT values of TLM decreased to greater extent after preparing complex of TLM with CD’s i.e. 10.99 min, 10.72 min 10.79 min and 10.68 min for COB, KNB, COH and KNH respectively. Complexes prepared by coevaporation and kneading method exhibited enhanced dissolution profile and lower MDT values, were taken as an important paradigm for the formulation studies. Calculated f2 values in table 4 indicate that the release profile of COH and KNH is significantly different from pure TLM (f2 values 27.25 and 25.21) which explains that complexes with HP-β-CD gives better dissolution results than β-CD.

 

Formulation studies:

The complexes prepared by kneading and coevaporation method (KNH and COH) were studied for physical properties to judge its tableting suitability. In general, compressibility index values up to 15% and angle of repose between 25⁰ and 30⁰ often found to result in good to excellent flow properties. Percent compressibility, angle of repose for complexes and physical properties of tablets made using these complexes are shown in table 5. These values indicated good compressibility and flow properties, making these samples suitable for tableting. The tablets prepared using complexes showed faster and reproducible release as compared to the tablets containing pure TLM and no CD’s. Tablets prepared using COH and KNH showed 79.38 and 81.04 % release in 45 min with t₅₀% of 12.36 min and 11.44 min, respectively (Figure 7) exhibiting better dissolution profiles as compared to tablets prepared using TLM alone and marketed telmisartan tablet (Telsar®).

 

Table 3.  DP _{30 min}, t_50% and MDT values for release of Telmisartan  from different samples in Phosphate buffer pH 7.5

 

 

Table 4. f₂ values for comparison between release profiles of Telmisartan  from complex and PM’s in Phosphate buffer pH7.5

 

 

 

 

Table 5. Physical properties of complexes and tablets of Telmisartan

 

^(a) n=3

 

These results clearly point out the advantage of improved aqueous solubility of TLM in its complex form, which can be formulated as tablets with better dissolution pattern. Release profiles of TLM from tablets containing TLM alone are significantly different from tablets containing COH and KNH as the f2 values were 34.43 and 32.24 respectively. MDT of TLM from tablets containing COH and KNH were (12.34 and 11.91 min) significantly lower than that of tablets containing only TLM (table 3).

 

CONCLUSION:

Solubility studies showed a significant, linear increase in the aqueous solubility of telmisartan with increasing concentrations of β-CD and HPβ-CD. The highest improvement in solubility and in vitro drug release were observed in inclusion complex prepared with HPβ-CD by kneading method. Improvement in solubility and drug release of telmisartan were more with HPβ-CD as compared to β-CD. The findings suggest that prepared complex with HP-β-CD showed greater dissolution profile of TLM. Further similar improved dissolution with tablets formulated with HP-β-CD inclusion complex of TLM.

 

Fig 5: DSC thermograms of Telmisartan, CD’s and its complexes (a) TLM, (b) β –CD, (c) PMB, (d) COB, (e)KNB, (f) HP β –CD, (g) PMH, (h) COH, (i) KNH

 

Fig 6: In vitro dissolution profiles of Telmisartan, its physical mixture & complexes in Phosphate buffer pH7.5.

 

Fig 7: Release profiles TLM from conventional tablets containing only TLM and tablets containing KNH and COH in Phosphate buffer pH7.5.

 

ACKNOWLEDGEMENT:

We would like to thank Unichem Laboratories, Raigad India for gift sample of TLM and Gangwal Chemicals Pvt. Ltd. Mumbai (India), for providing β-CD and HPβ-CD. We acknowledge University of Pune for conducting PXRD and DSC studies of the samples.

 

REFERENCES:

1.        Karlberg BE, Lins LE, Hermansson K. Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension. TEES Study Group. J. Hypertension 1999; Feb; 17(2):293- 302.

2.        Ries UJ, Mihm G, Narr B, et al. 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor - antagonists: Synthesis, biological activity, and structure-activity relationships. J Med Chem 1993; 36:4040– 4051.

3.        Mallion JM, Siche JP, Lacourcière Y and the Telmisartan Blood Pressure Monitoring Group. ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild to moderate hypertension. J. Hypertension 1999;13:657– 664.

4.        Benson SC et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004 May; 43(5): 993-1002.

5.        Product Information: Micardis® HCT, telmisartan and hydrochlorothiazide.Boehringer Ingelheim, Ridgefield, Connecticut. (PI revised 11/2000) reviewed 11/2001.

6.        Proudfoot SG. Factors affecting bioavailability: factors influencing drug absorption from the gastrointestinal tract, Aulton, M.E. (ed.), Pharmaceutics, The Science of Dosage Form Design, Churchill Livingstone London, UK1991; pp. 135–173.

7.        Cappello, B., Clelia, D.M.,  Iervolino, M. and Miro, A.,  Improvement of Solubility and Stability of Valsartan by Hydroxypropyl-\boldbeta-Cyclodextrin Journal of Inclusion  Phenomena and Macrocyclic Chemistry, 2006, 54, 289-294.

8.        Patel R, Patel M. Solid-State Characterization and Dissolution Properties of Lovastatin Hydroxypropyl-β-Cyclodextrin Inclusion Complex, Pharm. Tech. Feb 2007, 72-81.

9.        G. Becket, L.J. Schep et. al. Improvement of the in-vitro dissolution of praziquantel by complexation with alpha, beta and gamma cyclodextrin. Int. J. Pharm. 1999; 179 (1): 65-71.

10.     Higuchi T, Connors K. Phase solubility techniques. Adv. Anal. Chem. Instru. 1965; 4:17–123.

11.     Moore JW, Flanner H. Mathematical comparison of dissolution profiles.  Pharm. Tech. 1996; 20: 64–74.

12.     US Food and Drug Administration, Guidance for Industry SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (FDA, Rockville, MD, 1997.

13.     Human Medicines Evaluation Unit, European Agency for the Evaluation of Medicinal Products (EMEA), Notes for Guidance on Quality of Modified-Release Products; A Oral Dosage Forms; B Transdermal Dosage Forms, Section 1 (Quality) (EMEA, London, UK, 1999).

14.     Reppas C, Nicolaides E. Analysis of drug dissolution data,  J.B. Dressman, and H. Lennerna’s (eds.), Oral drug absorption prediction and assessment, Marcel Decker, New York, 2000; pp. 229–254.

15.     Vueba ML, Batista LAE, de Carvalho, Veiga F,. Sousa JJ, Pina ME. Influence of cellulose ether polymers on ketoprofen release from hydrophilic matrix tablets. Eur. J. Pharm. Biopharm 2004; 58:1–59.

16.     Costa FO, Sousa JJS, Formosinho SJ. Comparison of dissolution profiles of Ibuprofen pellets, J. Controlled Release. 2003; 89 (2):199-212.

17.     Rinaki E, Dokoumetzidis A, Macheras P. The Mean Dissolution Time Depends on the Dose/Solubility Ratio, Pharm. Res. 2003;  20(3): 406- 408.

18.     Loftsson T, Magnusdottir AM, Masson JF, Sigurjonsdottir.. Self-association and cyclodextrin solubilization of drugs. J. Pharm. Sci. 2002; 91: 2307-2316.

19.     Loftsson T, Hreinsdottir D, Masson M. The complexation efficiency. J. Incl. Phenomena. 2007; 57: 545-552.

20.     Bonini M., Rossi S., Karlsson G., Almgren M, Nostro Lo, Baglioni P. Self-assembly of beta-cyclodextrin in water. Part 1. Cryo-TEM and dynamic and static light scattering. Langmuir 2006; 22: 1478–1484.

21.     Harry P, Hopkins Jr, Alexander C J.  Transfer gibbs free energies from H₂O to CH₃OH for a series of substituted phenyltropylium ions, Malachite Green, and Crystal Violet.  Journal of Solution Chemistry. 1976; 5 (4): 249-255.

22.     Corrigan OI, Stanley T. Mechanism of drug dissolution rate enhancement from β-cyclodextrin-drug systems. J. Pharm. Pharmacol. 1982; 34: 621–626.

 

 

 

 

 

Received on 30.08.2009          Modified on 25.10.2009

Accepted on 22.11.2009         © RJPT All right reserved