OR WAIT null SECS
The authors describe the development of an inclusion complex of GLZ and formulated an extended-release dosage form based on osmotic technology.
The earliest studies in the field of modified drug delivery date back to the 1950s. Since then, a large number of drug products, mainly in the form of tablets and capsules with controlled-release characteristics, have been introduced. Das and Das predicted a minimum growth of 9% per year for this market through 2007 (1). Various technologies have been investigated to achieve the different types of modified release (e.g., sustained, delayed, pulsatile, targeted, and programmed release). Regardless of the delivery type, the primary mechanisms associated with drug transport in these systems are diffusion, swelling, erosion, ion exchange, and osmotic-transport effect. These mechanisms have been investigated in several studies (2–7).
Glipizide (GLZ), a weak acid (pKa = 5.9) is practically insoluble in acidic environments, highly permeable, and insoluble in water (39 µg/mL). Oral absorption of GLZ is uniform, rapid, and complete; its bioavailability is nearly 100%, and its elimination half-life is 2–4 h (8).
Class II compounds such as GLZ comprise relatively lipophilic and water-insoluble drugs with saturated solubility ≤0.1mg/mL that, when dissolved, are well absorbed from the gastrointestinal tract. Commonly, drugs in this class have variable bioavailability because of the influence of formulation effects and in vivo variables on absorption (9). Scientists try various formulation techniques such as nanoparticles, the addition of surfactants, salt formation, and complexation to change the drugs to Biological Classification System Class I compounds (9–11). Complexation with cyclodextrins (CDs) has been widely used to improve the solubility and dissolution rate of poorly water-soluble drugs (12). CDs also enhance drugs' physical and chemical stability and eliminate unpleasant odors and tastes (13).
Many methods are available for determining the physical nature of an inclusion complex. The inclusion complex can be characterized in the solid state by techniques such as Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) (14). A complex prepared using the solvent-evaporation method in a 2:1 ratio of hydroxypropyl (HP)–β–CD to GLZ enhanced solubility and dissolution. The result could be used to formulate an osmotic-pump tablet.
In the 1970s, Theeuwas introduced an elementary osmotic-pump tablet (EOPT) (2). Because an EOPT is simple to prepare and drug release can be controlled over an extended period, interest in developing EOPTs increased over the past two decades. However, the generic EOPT is only suitable to deliver drugs of moderate solubility. Okimoto investigated osmotic-pump tablets for poorly water-soluble drugs (e.g., testosterone, prednisolone, and chlorpromazine) using sulfobutyl ether-β-cyclodextrin (SBE) 7m-β-CD as a solubilizer and osmotic agent (12, 15).
The authors aimed to develop a new EOPT of GLZ with proper accessorial material after making an inclusion complex of it with HP–β–CD to increase its solubility and deliver it over an extended period of time.
GLZ, microcrystalline cellulose, dicalcium phosphate, spray-dried lactose monohydrate NF, magnesium stearate, and talc were donated by Sword and Shield Pharmaceutical (Chhatral, Gujarat, India). The sample of HP–β –CD (molecular weight of 15000 Da) was a gift from Roquette (Lestrem, France). Sodium chloride and potassium chloride were purchased from S.D. Fine Chem (Mumbai). Various grades of hydroxypropyl methylcellulose (HPMC) were donated by Colorcon Asia Pacific (Singapore). All chemicals and solvents were of analytical-reagent grade.
Phase-solubility studies were carried out by adding 100 mg of drug to screw-capped vials containing various concentrations of a 25-mL aqueous HP–β –CD solution. The solutions were stirred continuously using an electromagnetic stirrer (Labstirrer, Remi Laboratory Instruments, Mumbai) at 25 °C and 37 °C and 300 rpm for 48 h. The solutions were filtered through 0.45-µm membrane filter. The filtrates were suitably diluted with simulated intestinal fluid at pH 6.8 simulated intestinal fluid (SIF) and analyzed spectrophotometrically (Shimazdu-1601 ultraviolet-visible spectrophotometer, Shimadzu, Kyoto, Japan), for the dissolved drug at 276 nm.
Preparation of complexes and physical mixtures. Solvent-evaporation method (coevaporation). An inclusion complex containing various weight ratios (i.e., 1:1, 1:2, and 2:1) of HP–β–CD to GLZ was prepared by the coevaporation method (16). The appropriate amount of HP–β–CD was added to a solution of GLZ (500 mg) in 0.1 N NaOH (10 mL). Next, the solvent was evaporated at 60 °C in an oven. The resulting residue was dried under vacuum at 40 °C for 3 h, ground in a mortar, and passed through an 80# sieve.
Kneading method. The required quantities of HP–β–CD, GLZ, and 0.1 N NaOH (1.5 mL) were mixed together in a mortar to obtain a homogeneous paste. GLZ was then added slowly. During grinding, a small quantity of 0.1 N NaOH (0.5 mL) was added to assist the dissolution of GLZ. The mixture was then ground for 1h. During this process, an appropriate quantity of 0.1 N NaOH was added to the mixture to maintain a suitable consistency. The paste was dried under vacuum at 50 °C for 24 h. The dried complex was pulverized and sieved through an 80# sieve.
Physical mixtures. Physical mixtures (PMs) having the same weight ratios of HP–β–CD to GLZ (i.e., 1:1, 1:2, and 2:1) were prepared by thoroughly mixing appropriate amounts of GLZ and HP–β–CD in a mortar until a homogeneous mixture was obtained.
Characterization of solid dispersion. Infrared (IR) spectroscopic analysis. FTIR spectra of moisture-free powdered samples were obtained using a spectrophotometer (FTIR-8300, Shimadzu) with the potassium-bromide pellet method (i.e., a 5-mg sample in 200 mg of potassium bromide). The scanning range was 400–4000 cm-1 , and the resolution was 1 cm-1 .
DSC analysis. DSC scans of the powdered samples were recorded using DSC with Thermal Data Analyzer trend-line software (DSC 60, Shimadzu). All samples were weighed and heated at a scanning rate of 10 °C/min under dry nitrogen flow (100 mL/min) between 50 and 300 °C. Aluminum pans and lids were used for all samples.
The complexes prepared by the kneading, coevaporation, and physical-mixture methods were assayed for GLZ content by the saturated shaking-flask method (17). Excess amounts of the complex were placed into 10-mL vials containing water. The vials were sealed and shaken for 24 h at room temperature. The solutions were filtered through a 0.45-µm membrane filter. The filtrates were suitably diluted and analyzed spectrophotometrically for the dissolved drug at 276 nm. All assays were performed in triplicate.
Wettability and dissolution studies
Wettability studies were performed using open tubes containing GLZ. Its PMs and inclusion complexes with HP–β–CD were placed with their lower capillary ends dipped into a solution of 0.05% w/v crystal violet and water. The upward migration of the colored front in the capillary tube was recorded as a function of time.
Dissolution studies were performed using Apparatus 2 of USP 30–NF 25 for 120 min. Samples equivalent to 5 mg of drug were added to the dissolution medium (i.e., 500 mL of demineralized water) at a temperature of 37 °C ± 0.5 °C, which was stirred at 50 rpm. Operators withdrew 5-mL samples at intervals of 10, 20, 30, 40, 60, 90, and 120min. The samples were filtered with Whatman filter paper #1 (Whatman International, Maidstone, UK), diluted with SIF, and analyzed at 276 nm using a spectrophotometer. The dissolution study was conducted in triplicate, and mean values were plotted.
Formulation of an elementary osmotic-pump tablet
Preparation of core tablet. The core tablets for the EOPT were prepared by direct compression. The GLZ complex was mixed with all the excipients and passed through an 80# sieve. The formulation was compressed into tablets with an average weight of 310 ±20 mg on a multitooling rotary tablet press (Remake Minipress-II MT, Karnavati Engineering, Kadi, India) fitted with 8-mm round, standard concave punches. Table I lists various core formulations of the GLZ complex. The core tablets were evaluated for various pharmacotechnical parameters.
Table I: Formulation of elementary osmotic pump core tablet (%/tablet). ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHORS.
Coating of core tablet. The core tablets were film coated with a semipermeable membrane of 2.5% w/v cellulose acetate (CA) with castor oil 20% (w/w total weight of CA) as a plasticizer using a conventional, laboratory-model, stainless-steel, 20-cm, pear-shaped, baffled coating pan with a pan-rotating rate of 25 rpm. Core tablets of GLZ were placed in the coating pan along with 100 g of filler tablets made using 9.6-mm round concave punches and containing lactose, dibasic calcium phosphate, starch paste, magnesium stearate, and talc. The inlet air temperature was about 60–70 °C. The manual coating procedure was used based on an intermittent spraying and drying technique. The coated tablets were dried overnight at 50 °C to remove the residual solvent. An orifice (500 µm) through the membrane was made by a mechanical driller.
In vitrodrug-release study of osmotic tablets. In vitro drug release was tested according to the USP 30–NF 25 guidance for modified-release products. The authors used Apparatus 2 at 37 ± 0.5 °C and 50 rpm, testing 500 mL of 0.1 N HCl for the first two hours, followed by 500 mL of SIF. The samples were analyzed at 276 nm. The drug-release study was conducted in triplicate, and mean values were plotted. For comparisons between dissolution profiles of different samples, the authors used Moore and Flanner's model independent mathematical approach of calculating a similarity factor f2 (18).
Scanning electron microscopy studies
To characterize the surface of coated tablets before and after dissolution studies, the authors used a scanning electron microscope (SEM). Before dissolution studies occurred, the sample coated tablets were examined for surface morphology by SEM (JSM-5600, Jeol, Tokyo). A small sample of the coating membrane was carefully cut from the exhausted shells after 24 h of dissolution studies and dried at 50 °C for 12 h. This sample was examined under SEM for surface-morphology changes after dissolution.
Figure 1: Phase-solubility study.
Results and discussion
Phase-solubility study. Figure 1 represents the effects of temperature on the solubility of GLZ in the presence of HP–β–CD. Table II shows the apparent stability constants (Ka) and thermodynamic parameters derived from Figure 1.
Table II: Thermodynamic parameters of GLZâHPâÎ²âCD.
The plots of drug solubility against the polymer concentration at the investigated temperatures indicate a linear relationship in the investigated polymer concentration range. The solubility of GLZ increased with temperature and carrier concentration.
The solubility of GLZ in pure water at 25 °C was 39 µg/mL. At the highest polymer concentration (50 mM/mL), the solubility increased approximately sixfold and fivefold at 37 °C and 25 °C, respectively.
The stability constant for the complexes at 37 °C, assuming a 1:1 stoichiometry, calculated from the slope of the initial straight portion of the solubility diagram, was 733 M-1 , which indicated a suitable and stable complex formation.
The ΔGtr° values indicate whether the reaction conditions are favorable or unfavorable for drug solubilization in the aqueous carrier solution. Negative Gibbs free-energy values indicate favorable conditions. ΔGt° and ΔHt° were negative for HP–β–CD, indicating that the transfer of the drug from pure water to polymer solutions is spontaneous. Furthermore, as the polymer concentration increases, ΔHt° decreases, which indicates that the process becomes more favorable with higher polymer concentrations.
DSC studies. Figure 2 shows DSC curves obtained for pure GLZ, HP–β–CD, their PMs, and solid dispersions prepared with HP–β–CD. Pure powdered GLZ showed a melting endotherm at 216.73 °C. A DSC scan of HP–β–CD showed a broad endotherm at 84.7 °C because of the presence of residual moisture in HP–β–CD. DSC thermograms of PM 2:1 and kneading method 2:1 exhibits both of these endothermic peaks, although the peak for HP–β–CD is barely discernable.
Figure 2: Differential scanning calorimetry spectra of glipizide and inclusion complexes. COE is coevaporation, KNE is kneading, and PM is physical mixing.
DSC thermgrams of coevaporation 2:1 showed no endothermic peak for GLZ, and the endothermic peak of HP–β–CD was appreciably broader. This result seemed to indicate the formation of an inclusion complex.
IR studies. To further characterize possible interactions between the drug and the polymeric carrier in the solid state, IR spectra were recorded. Figure 3 shows the spectra of all samples. The chemical interaction between the drug and the carrier often leads to identifiable changes in complexes' IR profiles. The spectrum of pure GLZ presented characteristic peaks 3325 and 3251 cm-1 (i.e., for the N-H asymmetric stretch), 1690 and 1650 cm-1 (i.e., for the C=O stretch), 1444 and 1332 cm-1 (i.e., for the C-N stretch), and at 1159 cm-1 (i.e., for the SO2 stretch). The authors noted the presence or absence of characteristic peaks associated with specific structural groups of the drug molecule. The FTIR spectra revealed that the drug was entrapped in the cyclodextrin cavity.
Figure 3: Fourier transform infrared spectra of glipizide and inclusion complexes. COE is coevaporation, KNE is kneading, and PM is physical mixing.
Solubility of complexes. The solubility of the drug was determined according to the above method. The solubility of GLZ in pure water at 25 °C was 39 µg/mL. Solid dispersions prepared by coevaporation had the highest solubility, as shown in Figure 4.
Figure 4: Solubility study of glipizideâHPâÎ²âCD complexes.
Wettability and in vitro drug release studies. Figure 5 shows the improvement in wettability of GLZ by physical mixing and solid dispersion with HP–β–CD. Coevaporation 2:1 showed the highest wettability in water (100%), compared with pure GLZ (23.6%) after 20 min.
Figure 5: Wettability study of GlipizideâHPâÎ²âCD complexes.
Dissolution of pure GLZ and all other prepared systems (i.e., complexes and PMs) were carried out in demineralized water. Table III reports the values for the percent of drug dissolved within 20 min (DP20min), mean dissolution time (MDT), and time to dissolve 50% of the drug (t50%). The data show that the onset of dissolution of pure GLZ is slow (DP20min value was 6.14%, and t50% > 2 h).
Table III: Statistical comparison of dissolution profile of inclusion complexes.
Figure 6 shows dissolution profiles of pure GLZ, its PM, and inclusion complexes with HP–β–CD over a period of 120 min. The dissolution rate of pure GLZ is low; 29.69% of the drug is dissolved in 120 min. Inclusion complexes of GLZ with HP–β–CD significantly enhanced the dissolution rate of GLZ within 120 min, compared with PM and pure GLZ. PM with HP–β–CD also improved GLZ's rate of dissolution. The highest improvement was obtained using a complex prepared through coevaporation.
Figure 6: Drug-release profile of glipizideâHPâÎ²âCD complexes.
MDT is the first datum for the cumulative dissolution process that provides an accurate drug-release rate. A high MDT value indicates great drug-retarding ability (18). The MDT of pure GLZ was high (99.64 min). This value decreased greatly after the authors prepared GLZ's inclusion complexes and PM with HP–β–CD, which indicated an increase in dissolution rate. Coevaporation 2:1 had the lowest MDT (12.91 min).
Comparisons between the release profiles of different samples of GLZ were made with similarity factor f2. Table III shows that the release profiles of GLZ from all samples (i.e., complexes and PMs of HP–β–CD) and from pure GLZ were dissimilar; f2 values for these comparisons were less than 50. Coevaporation 2:1, which had a better in vitro dissolution profile, lower MDT, and lower f2 values, was selected for further formulation of as an EOPT.
Formulation development of an EOPT. The dosage form was designed as a tablet core coated with a semipermeable membrane that had a preformed passageway. The core tablets consisted of a GLZ complex along with osmagent and other conventional excipients. The core compartment was surrounded by a semipermeable membrane. After administration, the core compartment absorbs aqueous fluids from the surrounding environment through the membrane. After coming into contact with the aqueous fluids, the GLZ complex dissolves, and the dissolved drug is released through the drilled orifice.
Core tablets were evaluated for various pharmacotechnical parameters. The tablets' hardness was in the range of 4.0–6.0 kg/cm2 . The percentage friability of all formulations was below 1%, which was within the prescribed limits. Friability directly affects tablet. In a weight-variation test, the pharmacopoeial limit for the percentage deviation of all the tablets was less than 7.5%. The tablets contained 97–102% of the labeled amount of GLZ, thus indicating drug-content uniformity.
Figure 7 shows that variations in the formulation of the core tablet had a marked influence on GLZ release. Variation in the amount of osmotic promoting agent and swelling polymer influenced the drug-release rate and the amount of drug released in 24 h. Tablets' release rate and cumulative release at 24 h were higher in formulations that included NaCl than in those that included KCl. Tablets that included HPMC K4M had a lower drug release rate than those that included NaCl and KCl. The release rate increased as the amount of NaCl or KCl increased. The more NaCl or KCl was incorporated into a tablet, the more water was absorbed, the more the core formulation could be liquefied, and the more GLZ was released. HPMC K4M played the role of a thickening agent and elevated the viscosity of the tablet. As a consequence, less GLZ was released from the EOPT. Incorporating HPMC K4M with NaCl or KCl in a tablet formulation resulted in a lower drug-release rate, but produced a constant release rate over an extended period.
Figure 7: In vitro drug-release profile of the elementary osmotic-pump tablet.
SEM. To investigate the changes in the membrane structure, the authors studied the surface of the coated tablets using SEM. Figure 8 shows SEM micrographs of the membrane surface of batch B before and after dissolution studies were performed.
Figure 8: a) Membrane structure of batch B before dissolution studies, and b) membrane structure of batch B after dissolution studies.
Figure 8a shows the membrane structure of batch B before dissolution studies were performed. The surface of the coated tablet was smooth before coming into contact with the aqueous environment, and the coats appeared to be free of defects. Figure 8b shows an SEM micrograph of an excised section of the top surface of the membrane after the dissolution study was performed. It exhibited a surface morphology similar to that in Figure 8a, suggesting that pores had not developed in the membrane or been affected by the in vitro drug-release profile.
The authors' experiment showed that the dissolution rate of GLZ increased when it was dispersed in HP–β–CD. The complex formation was confirmed by DSC and FTIR. The increased dissolution rate in systems containing HP–β–CD was likely the result of the increased wettability and dispersibility of GLZ. Examination of the EOPT indicated that the osmotic promoting agent and swelling polymer significantly affected the in vitro drug-release profile.
Ritesh B. Patel* is a lecturer, and Rakesh P. Patel is an associate professor, both at S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Ganpat Vidyanagar, Kherva, Mehsana-Gozaria Highway, PIN-382711, Gujarat, India, firstname.lastname@example.org. Madhabhai M. Patel is a principal of Kalol Institute of Pharmacy.
*To whom all correspondence should be addressed.
Submitted: Oct. 7, 2009. Accepted: Jan. 13, 2010.
1. N.G. Das and S.K. Das, supplement to Pharm. Tech. 27 (6), 10–16 (2003).
2. F. Theeuwes, J. Pharm. Sci. Technol. 64 (12), 1987–1991 (1975).
3. R.W. Korsmeyer et al., Int. J. Pharm. 15 (1), 25–35 (1983).
4. H. Khurahashi, H. Kami, and H. Sunada, Chem. Pharm. Bull. 44 (4), 829–832 (1996).
5. B. Narasimhan, Adv. Drug Deliv. Rev. 48 (2–3), 195–210 (2001).
6. T. Durig and R. Fassihi, J. Control. Release 67 (1), 37–44 (2000).
7. S.M .Herbig, J.R. Cardinal, and RW. Korsmeyer, J. Control. Release 35 (2–3), 127–136 (1995).
8. Goodman and Gilman's The Pharmacological Basis of Therapeutics, J.G. Hardman, L.E. Limbird, and A.G. Gilman, Eds. (McGraw Hill, New York, 10th ed., 2001), p. 1927.
9. G. Amidon, H. Lennernas, and V.A. Shah, Pharm. Res. 12 (3), 413–420 (1995).
10. J. Dressman, J. Butler, and J. Hempenstall, Pharm. Technol. 25 (7), 68–76 (2001).
11. D. Horter and J. Dressman, Adv. Drug Deliv. Rev. 46 (1), 75–87 (2001).
12. C. Fernandes, M. Vieira, and F. Viega, Eur. J. Pharm. Sci.15 (1), 79–88 (2002).
13. V.D. Mooter et al., Int. J. Pharm. 164 (1–2), 67–80 (1998).
14. K. Okimoto et al., J. Pharm. Res. 15 (10), 1562–1568 (1998).
15. K. Okimoto, R.A. Rajewski, and V.J. Stella, J. Control. Release 58 (1), 29–38 (1999).
16. C. Leuner and J. Dressman, Eur. J. Pharm. Biopharm. 50 (1), 47–60 (2000).
17. A. Avdeef, Adv. Drug Deliv. Rev. 59 (7), 568–590 (2007).
18. J.W. Moore and H.H. Flanner, Pharm. Technol. 20 (6), 64–74 (1996).