OR WAIT 15 SECS
The authors analyzed the effects of complexation as well as the levels of ammonium bicarbonate and crospovidone on tablet wetting time (WT), disintegration time (DT), and percent dissolution efficiency at 60 min (%DE60).
Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of pain and inflammation associated with rheumatoid arthritis and osteoarthritis (1). The incidence of gastrointestinal ulceration associated with nabumetone appears to be lower than for other NSAIDs, suggesting that the drug may be a preferential inhibitor of cyclooxygenase-2 (2). Because the drug exhibits poor aqueous solubility, researchers have attempted to improve its solubility using various techniques (3, 4). Efforts also have been made to elicit a rapid onset of therapeutic effect by formulating the drug as an effervescent chewable tablet and as a compressed annular tablet with molded tablet triturate (5, 6).
Although conventional tablets are widely accepted oral solid-dosage forms, pediatric, geriatric, and bedridden patients experience difficulties in swallowing them. Moreover, for poorly soluble drugs, dissolution of the drug from the tablet is the rate-limiting step in the process of drug absorption (7). Because the rate and extent of drug absorption is determined by the rate and extent of drug dissolution from tablets, drugs with poor aqueous solubility as a result of erratic or incomplete absorption from the gastrointestinal tract are known to pose potential bioavailability problems (8).
Because nabumetone is practically insoluble in water, its absorption is expected to be dependent on dissolution rate (9). This study attempts to resolve this problem by formulating the drug previously complexed with β-cyclodextrin (β-CD) as a porous rapidly dispersing tablet. These tablets were intended to disintegrate quickly and dissolve completely to facilitate complete drug absorption following oral administration. Inclusion complexes have been used successfully to improve solubility, dissolution, and bioavailability of poorly soluble drugs (10–14).
Materials and methods
Materials. Nabumetone was donated by Micro Labs (Bangalore, India). β-CD manufactured by Roquette Freres (Lestrem cedex, France) was donated by Signet Chemical Corp., (Mumbai, India). Crospovidone (polyplasdone XL) and mannitol (Paerlitol) were samples from Zydus Health Care Ltd., (Bangalore). The other samples of ammonium bicarbonate, saccharine sodium, and polyvinyl pyrollidone-K30 (PVP-K30) were of analytical grade and purchased from S.D. Fine Chemicals (Mumbai).
Phase solubility studies.Phase solubility studies were performed in triplicate at room temperature (25 °C) according to the method reported in the literature (10). Excess amounts of nabumetone were added to distilled water containing various concentrations of β-CD (0.3–1.5 mM) in a series of stoppered volumetric flasks and shaken for 72 h on a rotary shaker (Secor Laboratory Instruments, New Delhi, India). The resulting suspensions were filtered through 0.45-μm filter, diluted suitably, and assayed spectrophotometrically (model UV 1700 PC Shimadzu Corp., Kyoto, Japan) at 270 nm using reagent blanks prepared with the same concentrations of β-CD in distilled water. The apparent stability constant (Ks) of the complexes was calculated from the slope and the intercept of the phase solubility diagram using Equation 1:
Preparation of the complexes. The drug β-CD complexes were prepared using the kneading method (10). Nabumetone was mixed with equimolar quantities of β-CD in a mortar with a small amount of water and kneaded for 45 min to obtain a homogeneous paste. The resulting paste was dried in an oven at 45 °C for 48 h, and the solid obtained was ground and sieved through a 150-μm sieve. A physical mixture of the drug and β-CD at a 1:1 molar ratio prepared by simple mechanical admixing was used as a reference during characterization of the kneaded complex.
Fourier transform infrared (FTIR)spectrophotometry. The samples were powdered and mixed with dry powdered potassium bromide. The mixtures were taken in a diffuse reflectance sampler and infrared spectra of the drug, β-CD, and the inclusion complexes were recorded by scanning the 400–4000 cm–1 wavelength region in an FTIR spectrophotometer (model 460 Plus, Jasco, Japan).
Differential scanning calorimetry (DSC). Samples of the drug, β-CD, physical mixture, and the kneaded complex were taken in flat round-bottomed aluminum pans and heated in a temperature range of 50–300 °C at a rate of 10 °C per minute with nitrogen purging (50 mL/min) using alumina as the reference standard in a differential scanning calorimeter (model pyris-1, Perkin Elmer, LLC, Norwallk, CT).
Powder x-ray diffraction (PXRD). The diffraction studies of the drug, β-CD, physical mixture, and the kneaded complex were performed in a powder x-ray diffractometer with a vertical goniometer (model PW 1050/37, Philips, the Netherlands). PXRD patterns were recorded using monochromatic CuK a radiation with nickel filter at a voltage of 40 kV and a current of 20 mA between 5 and 308 2θ values.
An eight-run 23 factorial design consisting of three factors at two levels was set up to produce porous rapidly dispersing tablets of nabumetone (15). The levels of ammonium bicarbonate (X1) and crospovidone (X2) were the numerical factors analyzed, whereas the effect of complexation (X3) was investigated as the categorical factor. The responses evaluated were the disintegration time (Y1), wetting time (Y2), and dissolution efficiency at 45 min (Y3). The selected factors and their corresponding levels as per the design are listed in Table I.
Table I: Factors and their corresponding levels as per 23 factorial design*.
Tablet compression. A total of eight batches of dispersible tablets containing the drug either in the free or the precomplexed form were produced by a wet granulation procedure using varying amounts of ammonium bicarbonate and crospovidone (16). The raw materials were passed through sieve #100 (150 μm) before dry mixing. The mixtures of ammonium bicarbonate, crospovidone, mannitol, sodium saccharine, and drug or its complex were dry mixed for 15 min in a glass mortar and pestle to obtain a uniform blend. The powder blend was granulated for 5 min using a solution of poly(vinylpyrrolidone) K-30 in ethanol (10% w/v) and passed through sieve #22 (710 μm). The granules obtained were air dried and passed through the same sieve to break the lumps.
The dried granules passing through sieve #22 (710 μm) and retained on sieve #44 (355 μm) were lubricated with magnesium stearate and talc in a plastic bag for 5 min. The lubricated granules were compressed to tablets on a rotary tablet press (model Rimek RSB-4 mini press, Karnavati Engineering, Ahmedabad, India) using 13-mm round, flat-faced bevelled-edge tablet B tooling. Each tablet weighing 650 mg contained 50 mg of the drug in the free or in the precomplexed form. The compressed tablets were dried in a vacuum oven (Lab model, Servewell Instruments, Bangalore, India) at 60 °C to a constant weight. The composition of the different batches of tablets produced as per the 23 factorial design is shown in Table II.
Table II: Composition of model formulations of nabumetone dispersible tablets prepared as per 23 factorial design.
Disintegration time was recorded following the Indian Pharmacopeia procedure in a USP XXIII disintegration tester (model ED-2L, Electrolab Ltd (I) Ltd., Mumbai) (17). One tablet was placed in each tube of the apparatus using distilled water maintained at 37 ± 0.5 °C as a disintegrating medium. A conventional method was used to measure the wetting time and capillarity of the orodispersible tablets (18). Wetting time was recorded at 25 °C in triplicate by placing a tablet in a 6.5-cm Petri dish, which contained 10 mL of water.
Weight uniformity was determined with a digital balance (model 220BL, Shimadzu Corporation, Kyoto, Japan) according to the official method (19). Tablet hardness and thickness were evaluated using a hardness tester (Scientific Engineering Corp., Delhi, India) and digimatic caliper (Mitutoyo Corp., Japan), respectively (20). For each batch, tablet friability was determined in an automated USP friabilator (model EF-2, Electrolab (I) Ltd., Mumbai). Tablet content uniformity was computed from the assay values in 2% w/w solution of sodium lauryl sulphate (9).
In vitro dissolution studies were carried out in triplicate for 45 min in USP dissolution-rate test Apparatus II (model TDT-06T, Electrolab (I) Ltd., Mumbai), as per the official method (9). Dissolution media consisting of 900 mL of 2% w/w SLS in distilled water was maintained at 37 ± 0.5 °C and a stirring speed of 50 rpm. Samples were withdrawn at time intervals of 15 min, filtered through 0.45-μm filter, suitably diluted, and analyzed spectrophotometrically at 270 nm using 2% w/w solution of SLS as a reagent blank. Percent dissolution efficiency at 45 min, used to compare the dissolution profiles of the model formulations, was calculated using Equation 2:
in which Yt stands for percent of drug dissolved at time T and Y100 denotes 100 % dissolution (21). The integral representing the area under the dissolution curve between time zero and time T was computed using Graph Pad Prism version 4.02 (GraphPad Software., San Diego, CA).
Regression analysis. The targeted response parameters were statistically analyzed by applying one-way analysis of variance (ANOVA) at 0.05 level in Design-Expert 7.1.3 demo version soft ware (Stat-Ease Inc.., Minneapolis, MN). Individual parameters were evaluated using the F test, and polynomial models of the form indicated in Equation 3 were generated for each response parameter.
in which Y is the level of the measured response, β0 is the intercept, and β1 to β5 are the regression coefficients. X1 and X2 stand for the main effects; X1 X2, X2X3, and X1X3 are the two-way interactions between the main effects, and X1X2X3 represents the three way interaction. Mathematical models containing only the significant terms were generated for each response parameters using multiple linear regression analysis (MLRA) and ANOVA. The models generated were used to construct the three-dimensional graphs in which response parameter Y was represented as a function of X. The effect of independent variables on each response also was visualized from the contour plots.
Validation of the mathematical models. The mathematical models representing the response parameters were validated by developing a new formulation with a combination of factors within the experimental domain (16). Constraints such as minimizing the disintegration time (DT) and maximizing the wetting time (WT)and dissolution efficiency at 60 min (%DE60) were set to locate the optimum settings of the independent variables in the new formulation. The new formulation was evaluated for the responses, and the experimental values obtained were compared with those predicted by the mathematical models.
Results and discussion
Solubility results. The phase-solubility diagram obtained was classified as AL type because the apparent solubility of nabumetone increased linearly (R2 5 0.968) with β-CD concentration over the entire concentration range studied, thereby suggesting the formation of a water soluble complex. A slope value of less than 1.00 indicated that an inclusion complex in a molar stiochiometric ratio of 1:1 was formed between the drug and β-CD in solution. The stability constant (411.76 M–1), computed from the slope and intercept of the phase solubility diagram, indicated considerable interaction between the hydrophobic drug and the hydrophobic cavity of β-CD. The values of stability constants described in the literature ranged from 100 to 20,000 M–1 for drug β-CD complexes (22).
Spectral analysis. The IR spectra of the drug, β-CD, and the kneaded complex are portrayed in Figure 1. The IR spectra of the complex revealed that many functional groups of the drug might have interacted with β-CD. A low-intensity peak assignable to the drug carbonyl stretching appeared to have shifted from 1705 cm–1 to 1690 cm–1 in the spectra of the kneaded complex. This displacement and reduction of the peak intensity suggested the possibility of the hydrogen-bond formation between the -C=O of the guest molecule and the hydroxyl functional group of β-CD. The spectra of the complex showed that the broad β-CD band between 3900 and 2900 cm–1 overlapped the drug characteristic peaks as a result of -CH- aromatic stretching and -CH- aliphatic stretching of the same region. A similar overlapping of the drug characteristic peaks by the β-CD band on complexation has been published (23).
Figure 1: FTIR spectra of (a) nabumetone, (b) b-cyclodextrin, (c) physical mixture, and (d) kneaded complex. All figures are courtesy of the authors.
The drug peaks at 1645 cm–1 resulting from skeletal vibrations of -C=C- bonds in the aromatic ring decreased in the intensities in the spectra of the complex, thereby indicating considerable drug and β-CD interaction. These spectral observations suggest that the vibration and bending of the drug molecule might be restricted because of complexation as the aromatic ring of the drug was inserted in the β-CD cavity.
Differential scanning calorimetry.. The endothermic peak at 80 °C in the DSC scan of the drug represented the melting-point transition of the crystalline drug (see Figure 2). The broad band that appeared between 110 °C and 140 °C in the thermogram of β-CD can be attributed to a loss of water or a molecular dehydration process. The reduced area of the drug endothermic peak in the DSC spectra of the complex indicated considerable interaction between the drug and β-CD, which substantially reduced the drug crystallinity. This reduction in the band area and the peak intensity indicates a reduction in the energy required for the melting transition. The β-CD dehydration band in the DSC scan of the kneaded product shifted to lower temperature between 90 and 130 °C. A similar shift in the β-CD dehydration band on complexation has been recorded (23).
Figure 2: DSC thermogram of (a) nabumetone, (b) b-cyclodextrin, (c) physical mixture, and (d) kneaded complex. All figures are courtesy of the authors.
Powder x-ray diffraction. There were 11 peaks in the PXRD spectra of nabumetone and 24 peaks in the diffractogram of β-CD when the samples were scanned between 0 and 30 2θ values (Figure 3). It has been reported that the total number of peaks in the kneaded product is the sum of the number of individual peaks provided there is no interaction (24). Accordingly, 35 peaks were expected to appear in the kneaded complex; however, the number of peaks that could be identified in the PXRD pattern of the complex was reduced to 23. Moreover, the maximum intensities of the peaks recorded in the PXRD pattern of the drug, β-CD, and the complex were 11,000, 4200, and 1600 counts, respectively. This reduction in the number and intensities of the peak in the diffractogram of the complex clearly demonstrated the decrease in drug crystallinity upon complexation.
Figure 3: Powder x-ray diffraction patterns of (a) nabumetone, (b) b-cyclodextrin, (c) physical mixture, and (d) kneaded complex. All figures are courtesy of the authors.
The results from the FTIR, DSC, and PXRD studies collectively indicate considerable interaction between the drug and β-CD that led to the reduction in the drug crystallinity. This decrease was responsible for the increased solubility of the kneaded complex when compared with the pure drug.
Several formulation variables influence the disintegration and dissolution of the tablets. A 23 factorial design was used to quantify the influence of different formulation variables on tablet properties of fast-dispersing tablets of nabumetone prepared by the conventional wet granulation procedure. Ammonium bicarbonate was used as a subliming agent, whereas crospovidone was used as a super disintegrant. Mannitol was incorporated as a filler to improve the palatability of the tablets, whereas saccharine sodium was used as a sweetener. The effects of complexation in addition to the levels of subliming agent and disinte grant on the tablet wetting, disintegration, and dissolution were systematically analyzed using ANOVA and the F test.
Table III:Physical properties of model formulations of nabumetone dispersible tablets prepared as per 23 factorial design. All figures are courtesy of the authors.
The Indian Pharmacopeia has stated a maximum disintegration time of 3 min for dispersible tablets (19). With the aim to develop a rapidly dispersible tablet formulation that would comply with the official monograph, a set of preliminary trials were undertaken to establish the range of the each formulation variable. Based on the trials undertaken, the lower and upper levels of the ammonium bicarbonate were retained at 10% and 30% of the tablet weight, respectively. The levels of crospovidone were varied between 5% and 15% of the tablet weight, respectively, during the run. Factors such as the amount of drug in the tablet, tablet hardness, and tablet thickness that were found to influence the response parameters were maintained constant during the run. Considering the poor aqueous solubility of the drug, tablets were produced with 50 mg of nabumetone to ensure a sink condition during dissolution testing.
Table IV: Response parameters of dispersible tablets of nabumetone prepared as per 23 factorial design. All figures are courtesy of the authors.
The physical properties and response parameters of the different batches of model formulations are listed in Table III and Table IV, respectively. The disintegration time, percentage friability, weight, and content uniformity complied with official specifications.
Table V: Summary of ANOVA for the response parameters of the model formulations of dispersible tablets prepared as per 23 factorial design. All figures are courtesy of the authors.
Disintegration time. The results of the analysis of variance along with the mathematical models generated are summarized in Table V. The DT of various model formulations ranged from 35 ± 0.83 to 120 ± 0.63 and depended on the bicarbonate and crospovidone levels. The linear model generated for DT was significant with an F value of 537 (p, 0.0001) and an R2 value of 0.999. The negative influence of the levels of ammonium bicarbonate and crospovidone on DT was clearly evident in the three-dimensional plots (see Figure 4).
Figure 4: 3-D plots showing the effect of formulation variables on disintegration time of tablets containing (a) nabumetone, and (b) nabumetone b-cyclodextrin complex. All figures are courtesy of the authors.
DT decreased from 112.33 ± 3.44 s to 72.66 ± 2.78 s and from 91.33 ± 3.16 s to 35 ± 2.54 s at lower and higher levels of crospovidone, respectively, as the levels of bicarbonate increased in tablets containing the drug (see Figure 4a). This decrease in DT occurs because higher levels of subliming agent render the tablet more porous, which permits the water to contact with the disintegrant quickly, thereby causing rapid tablet disintegration. Reduction in DT with increase in the amounts of subliming agent has been reported previously when camphor was used as a subliming agent (25).
The plot illustrates that DT decreased from 112.33 ± 3.44 s to 91.33 ± 3.16 s and from 72.66 ± 2.78 s to 35 ± 2.54 s at lower and higher levels of bicarbonate, respectively, as the crospovidone increased. The three-dimensional plot revealed that the effects of bicarbonate and crospovidone on DT were more pronounced at higher levels. This result could be attributed to quick water uptake and rapid swelling of the super disintegrant at higher levels. A reduction in the DT of orodispersible tablets with an increase in the levels of crospovidone has been cited in the literature (26). The corresponding contour plots depict a nonlinear relationship between the two variables on DT and suggests that the DT can be minimized using high levels of subliming agent and disintegrant.
DT decreased from 121.66 ± 4.52 to 81.33 ± 3.78 s and from 99.66 ± 4.12 s to 41.33 ± 2.14 s at lower and higher levels of crospovidone, respectively, as the levels of bicarbonate increased in tablets containing the complex (see Figure 4 b). The plot also shows that DT decreased from 121.66 ± 4.52 s to 99.66 ± 4.12 s and from 81.33 ± 3.78 s to 41.33 ± 2.14 s at lower and higher levels of bicarbonate, respectively, as the levels of crospovidone increased. In addition to the main effects, the interaction effect X1X2 had a negative influence on DT.
Wetting time. WT of different model formulations ranged from 21.33 ± 1.78 s to 73.66 ± 3.22 s and depended on the levels of bicarbonate and crospovidone. The predictor equation generated for WT was significant, with an F value of 887.48 (p < 0.0001) and an R2 value of 0.999. The three-dimensional plots demonstrate the negative influence of the bicarbonate and crospovidone levels on WT (see Figure 5).
Figure 5: Three-dimensional plots showing the effect of formulation variables on wetting time of tablets containing (a) nabumetone and (b) nabumetone b-cyclodextrin complex. All figures are courtesy of the authors.
WT decreased from 67.33 ± 2.41 s to 43.00 ± 2.10 s and from 54.66 ± 2.15 s to 21.33 ± 1.78 s at lower and higher levels of crospovidone, respectively, as the levels of bicarbonate increased in tablets containing the drug (see Figure 5a). This result can be attributed to the fact that high subliming agent levels left the tablet porous, which made the water easily accessible to the disintegrant and caused rapid tablet wetting.
The plots also show that WT decreased from 67.33 ± 2.41 s to 54.66 ± 2.15 s and from 43.00 ± 2.10 s to 21.33 ± 1.78 s at lower and higher levels of bicarbonate, respectively, as the crospovidone increased. The effects of bicarbonate and crospovidone on WT were more evident at higher levels than at lower levels as demonstrated by the three-dimensional plot. This result could be attributed to a rapid water uptake by the super disintegrant at higher levels.
WT decreased from 73.66 ± 3.22 s to 48.33 ± 2.32 s and from 60.66 ± 3.41 to 25.00 ± 1.52 s at lower and higher levels of crospovidone, respectively, as the levels of bicarbonate increased in tablets containing the complex (see Figure 5b). The plot also shows that WT reduced from 73.66 ± 3.22 s to 60.66 ± 3.41 s and from 48.33 ± 2.32 s to 25.00 ± 1.52 s at lower and higher levels of bicarbonate, respectively, as the levels of crospovidone increased. In addition to the main effects, the interaction effect X1X2 also had a negative influence on WT.
Dissolution efficiency. DE at the end of 45 min (%DE45) of the tablets containing the drug varied from 37.93 ± 1.05 to 41.21 ± 0.71, whereas tablets containing the complex exhibited %DE45 ranging between 61.20 ± 1.84 and 66.50 ± 1.52. The linear model generated for %DE45 was significant with an F value of 408.05 (p < 0.0001) and R2 value of 0.9885. Complexation was the lone factor that significantly influenced %DE45. The lack of any significant influence of the levels of ammonium bicarbonate and crospovidone on %DE45 of the tablets was clearly demonstrated in the three-dimensional plots shown in Figure 6. Complexation of the drug with β-CD, which improved drug solubility, was the major contributing factor responsible for the enhanced dissolution rate and the value of %DE.
Figure 6: Plots showing the effect of formulation variables on dissolution efficiency of tablets containing (a) nabumetone and (b) nabumetone b-cyclodextrin complex. All figures are courtesy of the authors.
The mathematical models representing the response parameters were validated by preparing a new formulation with a combination of factors within the experimental domain. The formulation was evaluated for the disintegration wetting and in vitro dissolution. Table VI lists the value of the observed responses and those predicted by mathematical models. The prediction error for the response parameters ranged from 3.39 to –2.44%. The low values of error prove the abilities of the generated mathematical models and reveal the capabilities of multiple linear regression analysis and analysis of variance in predicting the performance of the new formulation.
Table VI: Composition of the optimized formulations and comparison of the experimental values of the response parameters with the predicted values. All figures are courtesy of the authors.
In this study, the enhancement of nabumetone solubility was possible by complexation with β-CD. Various solid-state characterization techniques confirmed the formation of the drug β-CD inclusion complexes. A 23 factorial study performed indicated that complexation, amounts of ammonium bicarbonate, and crospovidone played a vital role in the production of dispersible tablets with desirable wetting, disintegration, and dissolution. The results obtained indicate that factorial studies can be successfully used to quantify the effect of several formulation and processing variables on tablet properties, thereby minimizing the number of experimental trials and reducing formulation development cost.
The authors are grateful to Sri Prabhakar Kore, Chancellor, KLE Academy of Higher Education and Research, Deemed University, Belgium for providing facilities to carry out the research work. The authors also thank Microlabs (Bangalore) for the gift samples of nabumetone and Signet Chemical Corp. (Mumbai) for the gift samples of β-cyclodextrin.
H.N. Shivakumar, PhD,* is a professor at the department of pharmaceutical technology, K.L.E.S's College of Pharmacy, Bangalore, India, firstname.lastname@example.orgB.G. Desai is a professor and head of the department of pharmaceutical technology, K.L.E.S's college of pharmacy. S. Narasimha Murthy, PhD, is an assistant professor at the department of pharmaceutics, The University of Mississippi (University, MS). Ashish Sharma is a clinical research associate at Pharmanet Clinical Service, Bangalore, India.
*To whom all correspondence should be addressed.
Submitted: Jan. 19, 2007. Accepted:Mar. 7, 2007
1. A. Burke, E. Smyth, and G.A. Fritzgerald "Analgesic–Antipyretic Agents; Pharmacotherapy of Gout," in The Pharmacological Basis of Therapeutics, L.L. Burton, J.S. Laso, and K.L. Parker Eds. (McGraw-Hill Medical Publishing Division, New York, 11th ed. 2006), pp. 671–715.
2. S.C. Sweetman "Analgesics and Anti-Inflammatory Drugs and Antipyretics," in The Complete Drug Reference (Pharmaceutical Press, London, 34th ed. 2005), pp. 1–115.
3. L. Chelakara et al., "Spherical Agglomeration of Mefenamic acid and Nabumetone to Improve Micromeritics and Solubility: A Technical Note," AAPSPharm SciTech. 7, Article 48 (2006).
4. N. Goyenechea et al., "Interaction of Nabumetone with Cyclodextrin in Solution and Solid State," J. Inclusion Phenomena Macrocyclic Chem. 44 (4), 283–288 (2002).
5. B.I. James, M.D. Roy, and C.P. Laurence, US Patent No. 5962022, (1994).
6. H. Jane et al., US Patent No. 6863901, (2005).
7. B. Hoener, and L.Z. Benet, "Factors Influencing Drug Absorption and Drug Bioavailability," in Modern Pharmaceutics, G.S. Banker and C.T. Rhodes. Eds. (Marcel Dekker Inc., New York, 3rd ed., 1996), pp. 121-154.
8. H.M. Abdou, "Methods for Enhancement of Bioavailability" in Dissolution, Bioavailability and Bioequivalence, A. Gennaro et al., Eds. (Mack Publishing Company, Easton, Pennsylvania, 1989), pp. 455–476.
9. "Nabumetone" in United States Pharmacopeia 27 (United States Pharmacopeial Convention Inc., Rockville, MD, Asian edition. 2004), pp. 1268.
10. G. Zingone, and I. Rubessa, "Preformulation Studies of the Inclusion Complex Warfarin-β-Cyclodextrin," Int. J. Pharm. 291, 3–10, (2005).
11. S. Tommasini et al., "Impovement in Solubility and Dissolution Rate of Flavonoids by Complexation with β-Cyclodextrin," J. Pharm. Biomed. Anal. 35, 379–387 (2004).
12. S. Rawat and S.K. Jain, "Solubility Enhancement of Celecoxib using β-Cyclodextrin Inclusion Complexes," Eur. J. Pharm. Biopharm. 57, 263–267 (2004).
13. X. Wen et al., "Preparation and Study the 1:2 Inclusion Complex of Carvedilol with b-Cyclodextrin," J. Pharm. Biomed. Anal. 34, 517–532 (2004).
14. A.M. Saetern et al., "Effect of Hydroxypropyl-b-Cyclodextrin-Complexation and pH on Solubility of Camptothecin," Int. J. Pharm. 284, 61–68 (2004).
15. "Factors Influence Studies," in Pharmaceutical Experimental Design, G.A. Lewis, D. Mathieu, and R. Phan-Tan-Luu, Ed. (Marcel Dekker Inc, New York, 1999), pp. 79 –150.
16. M. Gohel et al., "Formulation Design and Optimization of Mouth Dissolve Tablets of Nimesulide using Vaccum Drying Technique," AAPS PharmSciTech 5, Article 36, (2006).
17. "Disintegration Test" in Pharmacoepia of India (Controller of Publications, Ministry of Health and Family Welfare, New Delhi, 4th ed., 1996), pp. A–80.
18. S. Schiemeier, and P.C. Schmidt, "Fast Dispersible Ibuprofen Tablets," Eur. J. Pharm. Sci. 15, 295-305, (2002).
19. "Tablets" in Pharmacoepia of India (Controller of Publications, Ministry of Health and Family Welfare, New Delhi, 4th ed., 1996), pp. 734–736.
20. G.S. Banker GS and N.R. Anderson, "Tablets," in The Theory and Practice of Industrial Pharmacy, L. Lachman, H.A. Lieberman, and J.L. Kanig, Ed. (Varghese Publishing House, 3rd ed., Mumbai, India, 1991), pp. 293–345.
21. K.A. Khan, "The Concept of Dissolution Efficiency," J. Pharm. Pharmacol. 27, 48–49 (1975).
22. V.J. Stella and R.A. Rajewski, "Cyclodextrins: Their Future in Drug Formulation and Delivery," Pharm. Res. 14, 556–567 (1997).
23. L.S. Koester et al, "Influence of b-Cyclodextrin Complexation on Carbamazepine Release from Hydroxypropyl Methylcellulose Matrix Tablets," Eur. J. Pharm. Biopharm. 55, 85–91 (2003).
24. K.S. Aithal, N. Udupa, and K.K. Sreenivasan, "Physicochemical Properties of Drug–Cyclodextrin Complexes," Indian Drugs 32, 293–305 (1995).
25. K. Kiozumi et al., "New Method of Preparing High-Porosity Rapidly Saliva Soluble Compressed Tablets using Mannitol with Camphor, a Subliming Material," Int. J. Pharm. 152, 127 –131 (1997).
26. D.M. Patel, "Studies in Formulation of Orodispersible Tablets of Rofecoxib," Ind. J. Pharm. Sci. 66, 621–625 (2004). PT