Research Paper Enhanced Dissolution Rate of Glipizide by a Liquisolid Technique

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1 Hitendra S. Mahajan et.al. : Enhanced Dissolution Rate of Glipizide by a Liquisolid Technique 1205 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January March 2011 Research Paper Enhanced Dissolution Rate of Glipizide by a Liquisolid Technique Hitendra S. Mahajan*, Manoj R. Dhamne, Surendra G. Gattani, Ashwini D. Rasal and Hannan T. Shaikh R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur , Dist-Dhule, Maharashtra, India. ABSTRACT: This study aims to prepare immediate release glipizide liquisolid tablets using Avicel PH-2 and Aerosil 200 as the carrier and coating material respectively to increase dissolution rate of poorly soluble glipizide. This study also aims to evaluate treated Gellan gum as disintegrant in the preparation of liquisolid tablets. The solubility of glipizide was increased by use of liquisolid technique. The glipizide liquisolid tablets were evaluated for characteristics like drug content, friability, hardness, disintegration time, thermal analysis, X-ray diffraction (XRD) study and dissolution rates. The dissolution patterns of glipizide liquisolid tablets, carried out according to USP paddle method, and were compared with their commercial counterparts. The results obtained shows that all glipizide liquisolid tablets exhibits higher dissolution rates than those of marketed glipizide tablets. Dissolution rates increases with increasing concentration of liquid vehicles and maximum drug release achieved by formulations containing Polyethylene glycol 400 (PEG 400) as a liquid vehicle. The results of XRD and thermal analysis did not show any changes in crystallinity of drug and interaction between glipizide and excipients during the formulation process. KEY WORDS: Glipizide; liquisolid tablets; dissolution rate enhancement; non-volatile solvents Introduction With the recent advent of high throughput, screening and combinatorial chemistry, properties of many new chemical entities shifted towards higher molecular weight and increasing lipophilicity which results in decreasing aqueous solubility (Lipinski et al. 1997; Lipinski et al. 2000) and which in turn results in number of poorly soluble drug molecules and the formulation of these poorly soluble drug moieties for oral route, presents a great challenge for formulation and development. A great number of new and possibly beneficial chemical entities do not reach the public merely because of their poor oral bioavailability and hence inadequate dissolution. Poor aqueous solubility leads to poor dissolution and ultimately poor oral bioavailability (Rao et al. 2002). Over few decades, various approaches or techniques have been introduced to solve the problem of formulation of poorly soluble drug substances, with the original seek of enhancing drug dissolution characteristics, with different degrees of success. The liquisolid technique is a new and promising addition towards such a novel aim. The term liquisolid systems refers to powdered forms of liquid medications formulated by converting liquid lipophilic * For correspondence: Hitendra S. Mahajan, Tel: hsmahajan@rediffmail.com drugs, or drug suspensions or drug solutions of waterinsoluble solid drugs in suitable non-volatile solvent systems, into dry non-adherent, free-flowing and readily compressible powder admixtures by blending the suspension or solution with selected carriers and coating materials. The drug solution or suspension or may be liquid drug, called liquid medication was converted into free flowing, non-adherent, readily compressible and dry looking powder by simple addition of selected excipients, called carrier and coating materials. Microcrystalline Cellulose (Avicel PH 2) was used as carrier material because of porous nature and having good absorption properties for liquid medication. Silica powder (Aerosil 200) were used as coating material as it consists of very fine and highly adsorptive particles, which covers the wet carrier particles and shows dry-looking powder by adsorbing any excess liquid (Spireas and Bolton 1999). The antidiabetic agent, glipizide exhibits poor aqueous solubility. Glipizide belongs to class II of the biopharmaceutics classification system (BCS) (Jamzad and Fassihi 2006). Glipizide is a second-generation sulfonylurea that can acutely lower the blood glucose level in humans by stimulating the release of insulin from the pancreas and is typically prescribed to treat type II diabetes (non-insulin dependent diabetes mellitus) (Foster and Plosker 2006). Being a weak acid (pk a =5.9), glipizide is better absorbed from basic medium; however, at very low ph levels, the solubility of glipizide is minimal (Jamzad 1205

2 1206 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 and Fassihi 2006; Ammar et al. 2006). In this study, the effect of type and concentration of liquid vehicles on dissolution profile of glipizide liquisolid compacts was investigated. Interaction between the drug and excipients, and any crystallinity changes in liquisolid tablets were also studied by using X-ray diffractometry and differential scanning calorimetry (DSC) techniques. Material and Methods Glipizide was obtained from USV LTD. (USA), Commercial glipizide tablets 5 mg (CGT) Glynase (USV LTD., USA), Microcrystalline Cellulose 2 (Avicel PH 2) and Sodium Starch Glycolate (Explotab) both were obtained from JRS Pharma, (Rosenberg, Germany), Colloidal Silicon Dioxide-Aerosil 200 (Haffkin-Ajanta, India), Gellan Gum (GG) (CP Kelco, USA), Propylene Glycol (PG), Polyethylene Glycol 200 (PEG 200), Polyethylene Glycol 400 (PEG 400) all were obtained from Merck Germany. All other reagents and chemicals were of analytical grade. Solubility Studies To find out the best non-volatile solvent for dissolving or suspending of glipizide in liquid medication, solubility studies of glipizide were carried out in different nonvolatile solvents, i.e. PG, PEG 200 and PEG 400. Also simulated gastric fluid (ph 1.2) and phosphate buffer (ph 7.4) were used to study solubility behavior of glipizide. Saturated solutions were prepared by adding excess drug to the vehicles and shaking on the shaker (Remi International, India) for 24 hour at 25 0 C under constant vibration of speed 50 rpm. After this period the solutions were filtered through a 0.45 µm Millipore filter (Pall India Pvt. Ltd.), diluted with distilled water and analyzed by UVspectrophotometer (Shimadzu-1700, Japan) at a wavelength of 276 nm against blank sample (blank sample contained the same concentration of specific solvent used without drug). Three determinations were carried out for each sample to calculate the solubility of glipizide. Preparation of Treated Gellan Gum Treated gellan gum () powders were prepared by taking g Gellan Gum (GG; CP Kelco, USA) powder separately with sufficient distilled water (0 ml) and allowed to swell for 1 day at 37 ± C temperature. Then spread mechanically in petri-dish and allowed for drying up to three days in incubator (Remi, India) at 37 ± 1 0 C and pulverized by pulverizer (D.P. Pulverized industries, Mumbai, India) (Shiyani et al. 2008). Preparation of glipizide liquisolid tablets In order to attain optimal glipizide solubility in the liquisolid formulations, the concentration of the all three vehicles varied as, 5,, and (%W/W). The outline of the constituents of each of the formulae prepared is demonstrated in Table 1. Formulation Code Drug concentration in liquid vehicle (w) (% W/W) Table 1 The composition of different glipizide liquisolid e L f f R A vicel PH 2 q (Q) (in mg) Aerosil 200 h (q) (in mg) Distengrant (5%) Unit dose weight (in mg) a LS b LS c LS d LS-1T LS-2T LS-3T a LS-1: Liquisolid formulations containing Propylene Glycol (PG); b LS-2: Liquisolid formuations containing polyethylene Glycol 200 (PEG 200); c LS-3: Liquisolid formulations containing Propylene Glycol 400 (PEG 400); d T: Formuations containing treated gellan gum as a distintegrant; e L t :: Liquid load factor; f R: Ratio of carrier material (Q) to coating material (q) [R=Q/q]; g carrier material(q); k coating material (q)

3 Hitendra S. Mahajan et.al. : Enhanced Dissolution Rate of Glipizide by a Liquisolid Technique 1207 Both drug and liquid vehicle were mixed and heated to C with constant stirring, the solution was then sonicated for 15 min, until a homogenous drug solution was obtained (Fahmy and Kassem 2008) Then, the calculated weights of the resulting hot liquid medications were incorporated into the calculated quantities of the carrier material (Avicel PH 2; JRS Pharma, Rosenberg, Germany). After mixing, the resulting wet mixture was then blended with the calculated amount of the coating material (Aerosil 200; Haffkin-Ajanta, India) using a standard mixing process that was previously described by spireas et al (Spireas and Bolton 1999; Spireas 2002) to form simple admixture. The liquisolid mixture was then blended with 5% of the disintegrant, explotab or treated gellan gum (). The prepared liquisolid systems that were proven to have simultaneous acceptable flowability and compressibility were compressed into cylindrical tablets of desired weight using a multi-station tablet press machine (Rimek, India). The required quantities of excipients incorporated were calculated from the application of new formulation mathematical model of liquisolid systems as previously described by (Spireas and Bolton 1999; Spireas 2002; Spireas et al and Spireas et al. 1999). Characterization and Evaluation of Glipizide Liquisolid Tablets Drug content The drug content of the tablets was measured according to the IP Drug content uniformity of glipizide liquisolid tablets was carried out at 276 nm. For the purpose of content uniformity determinations, exactly weighed amounts of ten randomly drawn samples of all glipizide liquisolid tablets containing equivalent of 5 mg of the drug were dissolved in phosphate buffer (ph 7.4) and suitably diluted. The drug contents were determined at 276 nm, spectrophotometrically. Friability and Hardness The friability of the prepared formulae was measured using Digital Roche friabilator (Electrolab, India), and the percentage loss in weights were calculated and taken as a measure of friability. The hardness of the liquisolid tablets prepared was evaluated using Monsanto hardness tester, the mean hardness of each formula was determined. X-Ray Powder Diffraction (XRD Studies) The crystallinities of glipizide and glipizide liquisolid formulation were evaluated by XRD measurement recorded for glipizide, liquisolid formulation, physical mixture and excipients using x-ray diffractometer (PW37, Philips diffractometer) and Cu-Kα line as a source of radiation which was operated at the voltage 40 kv and the current 30 ma. All samples were measured in the 2θ angle range between 0 0 and 0 0 with a scanning rate of 3 0 /min and a step size of Thermal Analysis Differential scanning calorimetry (DSC) was performed on Glipizide, excipients, and liquisolid tablets. DSC measurement performed on DSC60 Shimadzu, Japan. Thermal behavior of the samples was investigated under a scanning rate of C/min, covering a temperature range of 50 to 300 C under inert atmosphere flushed with nitrogen at a rate of 0 C/min. Disintegration Test Randomly, six tablets were selected from each batch for disintegration test. Disintegration test was performed without disc in simulated intestinal fluid (37±0.5 0 C) using USP disintegration apparatus (Electrolab, India). The mean ± standard deviations (SD) of six tablets were calculated. Dissolution Studies The USP paddle method was used for all the in vitro dissolution studies. Dilute HCl, (ph 1.2) i.e. simulated gastric fluid without pepsin (ph 1.2) and intestinal fluid without pancreatin (phosphate buffer ph 7.4), and were used as dissolution media. The rate of stirring was 50 ± 2 rpm. The amount of glipizide was 5 mg in all formulations. The dosage forms were placed in 900 ml of gastric fluid (dilute HCl solution, ph 1.2) or intestinal fluid (phosphate buffer ph 7.4) and maintained at 37±0.1 0 C. At appropriate intervals (5,, 15, 20, 25, 30, 45, and 60 min), 5 ml of the samples were taken and filtered through a 0.45 μm Millipore filter. The dissolution medium was then replaced by 5 ml of fresh dissolution fluid to maintain a constant volume. The samples were then analyzed at 276 nm. The mean of 3 determinations was used to calculate the drug release from each formulation. For assessment and comparison, drug dissolution rates (D R ) of drug were used. For this, amount of drug (in μg) dissolved per min that presented by each tablet formulation during the first min were calculated as follows: D R = (M D) / 00 Where M is the total amount of glipizide in each tablet (in this study, it is 5,000 μg) and D denotes percentage of drug dissolved in first min.

4 1208 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 Statistical analysis All the data were statistically analyzed by analysis of variance or Turkey s multiple comparison tests. Results are quoted as significant where P < Results and Discussion The liquisolid technique proved to be a suitable method for solubility enhancement of poorly soluble glipizide. Liquisolid technique suggests that when the drug dissolved in the liquid vehicle is incorporated into a carrier material which has a porous surface and closely matted fibers in its interior as cellulose, both absorption and adsorption take place; i.e., the liquid initially absorbed in the interior of the particles is captured by its internal structure, and after the saturation of this process, adsorption of the liquid onto the internal and external surfaces of the porous carrier particles occur. Then, the coating material having high adsorptive properties and large specific surface area gives the liquisolid system the desirable flow characteristics (Spireas and Bolton 1999; Fahmy and Kassem 2008; Spireas 2002; Spireas et al and Spireas et al. 1999). Solubility Studies The solubility of glipizide in various solvents is given in Table 2. The table shows that the solubility of glipizide was increased by the presence of non-volatile solvents (PG, PEG 200, and PEG 400). The solubility increases in order as PEG 400 > PEG 200 > PG. The table also shows that an increase in ph resulted in an increase in the solubility of glipizide. Table 2 Solubility of glipizide in various solvents Solvent PG PEG 200 PEG 400 SGF (ph 1.2) SIF (ph 7.4) Solubility (gm/ml) Characterization and Evaluation of Glipizide Liquisolid Tablets The evaluation parameters drug content, friability, hardness and disintegration time were carried out for all glipizide liquisolid tablets. The results of these were quoted in Table 3. Drug Content All these liquisolid formulations complied with the test of glipizide content uniformity according to Indian Pharmacopoeia, as none of these formulations fall outside the limit of 98-2 %. This is because of R value ( R=Q/q), ratio of carrier (Q) to coating material (q) of contained by these formulations, which had sufficient concentration of carrier (avicel PH 2) that might lead to uniform distribution of drug by either adsorption onto, or absorption into carrier, therefore having more homogeneous distribution throughout the batch. Friability and Hardness All selected glipizide formulations meet the requirements of friability test, hence they are expected to show durability and withstand abrasion in handling, packaging and shipment. All liquisolid tablet formulations had acceptable hardness (Table 3). The optimized hardness for each liquisolid formulation was such that the tablets would be sufficiently hard to resist breaking during normal handling and yet soft enough to disintegrate after swallowing. XRD Studies It has been shown that polymorphic changes of the drug are important factors that may affect the dissolution rate and bioavailability. Therefore, it is important to study polymorphic changes of glipizide in liquisolid tablets. Figure1 shows the X-ray diffractograms of the pure glipizide and pure excipients, physical mixture (glipizide, Avicel, and silica) without liquid vehicle and liquisolid system. Glipizide diffractogram showed sharp peaks at 7.49, 11.08, 15.67, 18.67, and θ. Figure 1 shows that liquisolid and physical mixture formulations have the same diffraction pattern and there were no excess peaks except the peaks of Avicel and glipizide. It can be concluded that no alterations in crystallinity of glipizide or interaction between drug and excipients occurred during the formulation process. Thermal Analysis The results of DSC thermograms confirmed the above conclusion (Figure 2). Glipizide showed an endothermic

5 Hitendra S. Mahajan et.al. : Enhanced Dissolution Rate of Glipizide by a Liquisolid Technique 1209 peak around its melting point. The liquisolid and physical mixture formulations showed the same peak in this area, which indicates that there is no interaction between drug and excipients or changes in crystallinity of the drug during the formulation process. From the above finding, it can be concluded that the enhanced dissolution rate of glipizide liquisolid tablets is not due to the formation of complex between the drug and excipients or any changes in crystallinity of the drug. Fig. 1 X-Ray diffractogram of (A) Glipizide, (B) Liquisolid Formulation, (C) Physical mixture, (D) Treated Gellan Gum (), (E) Avicel PH-2, and (F) Aerosil 200 Fig. 2 DSC spectra of (A) Glipizide, (B) Liquisolid Formulation, (C) Physical mixture, (D) Treated Gellan Gum (), (E) Avicel PH-2, and (F) Aerosil 200

6 12 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 Disintegration Test Figures 1 and 2 signify that changing the disintegrant Explotab by had no significant effect on dissolution rates (D R ) of liquisolid formulations. The disintegration time test revealed that all the liquisolid formulae disintegrated in less than 5 minutes (Table 3). Hence we say that both the disintegrants have similar disintegration property, therefore can be a good alternative instead of explotab. Dissolution Studies To investigate the effect of type of non-volatile solvent on the dissolution rate of glipizide from liquisolid tablets, several formulations prepared using PG (LS-1), PEG 200 (LS-2) and PEG 400 (LS-3) with three different drug concentration as 5,, and (%W/W) in liquid medications. The dissolution profiles of these liquisolid formulations at different ph (1.2 and 7.4) are shown in Figure 3. The comparison of min dissolution rate of glipizide exhibited by liquisolid formulations and commercial glipizide tablet were shown in Figure 4. It was observed that all three liquid vehicles (PG, PEG 200, and PEG 400) used in liquisolid tablets, are able to increase the dissolution rate of glipizide from liquisolid tablets in comparison with commercial counterparts (Figure 3). Liquisolid tablets containing PEG 400 as liquid vehicle produces higher dissolution rates as compared to other liquisolid tablets containing PG and PEG 200 as liquid vehicle of the same drug concentration. Amount of drug released in first minutes from liquisolid formulations LS-1, LS-2, and LS-3 (% w/w liquid medication) were 44.13, 47.38, and 80.22, 83.22, 89.5 % at ph 1.2 and 7.4 respectively. The results clearly affirm that the liquisolid tablets containing PEG 400 (LS-3 formulations) had the highest percentage of cumulative release in first minutes. Therefore it is concluded from Figure 3 and 4 that formulations containing PEG 400 as liquid vehicle (LS-3) had highest glipizide dissolution rates in comparison to other formulations (LS-1 and LS-2). Figure 3 and Figure 4 signify that all the liquisolid formulae had higher drug dissolution rates (D R ), and larger amounts of drug dissolved in the first min than the commercial glipizide tablet. This observation could be explained according to the Noyes Whitney equation and the diffusion layer model dissolution theories, the dissolution rate of a drug (D R ) is equal to D R = (D / h) S (C S - C) Where h is the thickness of the stagnant diffusion layer formed by the dissolving liquid around the drug particles, D is the diffusion coefficient of the drug molecules transported through it, S is the surface area of the drug available for dissolution, C is the drug concentration in the bulk of the dissolving medium, and finally C S is the saturation solubility of the drug in the dissolution medium, and thus it is a constant characteristic property related to the drug and dissolving liquid involved. Since all of dissolution tests for formulations were done at a constant rotational paddle speed (50 rpm) and identical dissolution media, we can safely assume that the thickness of the stagnant diffusion layer (h) and the diffusion coefficient of the drug molecules remain almost identical. From the previous equation, the drug dissolution rate is directly proportional not only to the concentration gradient of the drug in the stagnant diffusion layer (C S - C), but also to its surface area (S) available for dissolution (Nokhodchi 2005; Javadzadeh et al. 2005; Spireas et al. 1998; Spireas et al. 1998). Table 3 Evaluation parameters of glipizide liquisolid tablets. Formula Mean Hardness (kg/cm 3 ) + SD a Fines (%) Friability No. of broken Tablets Average Glipizide Mean Content (%) + SD a Disintegration Time (min) + SD a LS None LS None LS None Table 3 Contd

7 Hitendra S. Mahajan et.al. : Enhanced Dissolution Rate of Glipizide by a Liquisolid Technique 1211 Formula Mean Hardness (kg/cm 3 ) + SD a Fines (%) Friability No. of broken Tablets Average Glipizide Mean Content (%) + SD a Disintegration Time (min) + SD a LS-1T None LS-2T None LS-3T None Fig. 3 Dissolution Profiles of glipizide from liquisolid tablets with different liquid vehicles compared with commercial glipizide tablet at different dissolution media.

8 1212 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 Fig 4. Comparison of -min dissolution rates of glipizide exhibited by liquisolid formulations and commercial glipizide tablet. Conclusion The wettability of the compacts by the dissolution media is one of the proposed mechanisms to explain the enhanced dissolution rate of glipizide from liquisolid tablets. The aim of improving dissolution rate and bioavailability of poorly soluble glipizide was successful because of increased wetting properties and solubility of drug in liquid vehicles. Use of mathematical model for calculating amounts of excipients helps in optimizing these formulations. Though all the three liquid vehicles used increase solubility of glipizide, PEG 400 was found as the best among them. Treated gellan gum was found to be an excellent disintegrating agent as compared to sodium starch glycolate. Acknowledgement Authors are thankful to USV LTD (India); CP Kelco division of Monsanto Company (USA); and JRS Pharma (Rosenberg, Germany) for gifting samples of bulk drug glipizide, gellan gum and microcrystalline cellulose, respectively. Authors express gratitude to the Principal (R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur) for providing necessary facilities to carry out this work. References Abdou H. Dissolution, Bioavailability and Bioequivalence, Edison Mack Publishing Co., Easton, PA, 1989, pp53 72.

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