INTRODUCTION:

An ideal drug delivery system should be able to deliver an adequate amount of drug, preferably for an extended period of time, for its optimum therapeutic activity. Most drugs are inherently not long lasting in the body, and require multiple daily dosing to achieve desired blood concentration to produce therapeutic activity. To overcome such problems, controlled release and sustained release delivery systems are receiving considerable attention from pharmaceutical industries world-wide ^1-2). Controlled release drug delivery systems not only prolong the duration of action, but also result in predictable and reproducible drug release kinetics ³⁾.

A controlled release product may be formulated to contain an immediately available dose to provide immediate action. This is followed by a more gradual and continuous release of subsequent doses to maintain the plasma concentration of the drug over an extended period of time. One obvious advantage of controlled release dosage forms is patient compliance ^4-6.

Delivery systems employing polymeric matrices are simpler and easier to fabricate. Such systems normally control the rate of release via a diffusion mechanism ⁷.

Delivery systems based on the principle of solid dispersion are multi-component mixtures of one or more active ingredients in an inert carrier or matrix in solid state. These are prepared either by dissolving the active ingredients in a solvent followed by drying, or by melting the active and inert ingredients together followed by solidification, or a combination of the two methods. In solid dispersion, the dissolution of active ingredient is affected by the presence of other components. Therefore carrier selection ultimately influences the dissolution characteristics of the dispersed drug ^8-9.

Hydroxypropyl cellulose (HPC) is a derivative of cellulose with both water solubility and organic solubility. It is also used in solid dispersion-type formulations of water-insoluble drugs. In polymer controlled surface erosion that provides a constant delivery of poorly soluble drugs via multi-unit erosion matrix, drug release was found to be proportional to matrix erosion. Hence matrix erosion could be used to predict drug release. This system consisted of Eudragit L-100 and Eudragit S-100 which were used as matrix-forming and release rate controlling polymers. These are anionic polymers based on methacrylic acid and methacrylic acid ester ¹⁰. The model drug (glipizide), Eudragit and polyvinylpyrrolidone (binder) were wet granulated and later palletized using an

extrusion/spheronization technique.

Figure 1: Comparative XRD spectra of GPZ powder, GPZ-PM and GPZ-CE.

The objective of the present study is to prepare solid dispersion granules by using glipizide (GPZ) and four grades of hydroxypropyl cellulose (HPC) having different molecular weights, and a precise control of the release rate of GPZ depending on the difference in molecular weight of HPC was attained. Later pellets containing GPZ or optimized solid dispersion of GPZ-HPC were prepared to determine the differences that were introduced by the solid dispersion.

Figure 2: Comparative DSC thermograms of GPZ powder, GPZ-PM and GPZ-CE.

MATERIALS AND METHODS:

Materials:

GPZ (known as oral hypoglycemic agent, 37.2 g of which dissolves in 1 ml of water at 37⁰C) was supplied by BAL Pharma, India. Three particle sizes of GPZ powder were used and the sizes of 355-250, 180-150 and 106-75 µm were collected as particle size L, M and S respectively. Four grades of HPC having different molecular weights were obtained from Nippon Soda Co. Ltd., Tokyo. The name of HPC grade, densities and mean molecular weight (MW) are shown in Table 2.1. Eudragit L 100-55, Eudragit S 100 were supplied by Rohm Pharma Polymers Division, Degussa Corporation, NJ. Kollidone 90 F (BASF, Inc., NJ). Avicel PH101 (FMC Corporation, Philadelphia, PA), triethyl citrate (Mortlex, Inc., NC). Other chemicals were of analytical grade. Double distilled water was used throughout the study.

Table 1. Density and Mean Molecular Weight of Used Polymers

Polymer Density (g/ml) MW

HPC HPC-SL 1.21 37500

HPC-L 1.21 105000

HPC-M 1.20 270000

HPC-H 1.21 357000

Preparation of Solid Dispersion Granules:

0.5 g GPZ and 9.5 g of each grade of HPC were dissolved in 400 ml ethanol, and then the solvent was evaporated to make the solid dispersion. The solid dispersion was ground and sieved. The fractions of 1000 µm -850 µm, 710-590 µm and 500-350 µm were collected as granule sizes L, M and S, respectively. L size granules were used in the cases was no description is given of the granule size ^11-14.

Figure 3: Comparative FT-IR spectra of GPZ powder, GPZ-PM and GPZ-CE.

Powder X-Ray Diffractometry:

Powder X-ray diffraction patterns were measured with a diffractometer (Geigerflex RAD-IB, Rigaku, Tokyo). The operation conditions were as follows: target, Cu; filter, Ni; voltage, 40 kV; current, 20 mA and scanning speed, 2θ = 4⁰/min.

Thermal Analysis:

Differential scanning calorimetry (DSC) curves were measured with a DSC instrument (SSC/560S, Seiko Instruments and Electronics, Tokyo). The heating rate was 4⁰C/min and nitrogen gas flowed at the rate of 70 ml/min.

IR Spectroscopy:

IR spectra were recorded with an infra red spectrophotometer (IR-810, JASCO, Tokyo), using KBr disks (about 10 mg sample for 100 mg drug KBr). The scanning range used was 4000 to 400 cm^-1 at a scan period of 1 minute.

Scanning Electron Microscopy:

An optical microscope (SMZ-10, Nikon, Tokyo) was used to observe the morphology of GPZ powder and solid dispersion granules.

Thermoscopy (Hot Stage Microscopy):

HSM of pure drug and solid dispersions were conducted using Mettler Toledo hot stage assembled on a Leica DMLP polarizing microscopy equipped with Leica DC300 (Germany) 0f 200 magnification using IM50 software. A small amount (2-4 mg) 0f sample was placed on a glass slide with a cover glass and heated at 3˚C/min. Changes in sample morphology were noted as a function of temperature.

Figure 4: Comparative optical micrographs of GPZ powder, GPZ-PM and GPZ-CE.

Determination of In Vitro Drug Release:

The dissolution behavior of GPZ from the granule and GPZ powder was observed with a flow sampling system (dissolution tester; DT-300, triple flow cell; DTF-359, spectrophotometer, UVITEC-340, Freund-JASCO), following the rotating basket method (JP XII), using 0.2 g of the granule sample (corresponding to 40 mg GPZ) and 900 ml of the dissolution medium at 37±0.5⁰C and a rotating basket at 100 rpm. The quantity of GPZ was determined with the absorbance at 276 nm. Buffer solutions of pH 1.2, 4.0, 5.5, 6.8, 7.4 and 8.0 were used for the dissolution medium. Release rate was calculated from release profiles by using linear least square method. Pellets prepared with selected solid dispersion and GPZ were also analyzed for dissolution using USP XXII Apparatus I in 900 ml of pH 7.4 phosphate buffer with ionic strength of 0.05 M, at 75 rpm and 37.0±0.5⁰C using 100 mg of pellets in each batch. Pellets obtained after dissolution were characterized for their shape and structure by an optical microscope (Nikon, Rutherford, NJ) ^17-20).

Stability Studies:

A six month accelerating condition stability test was carried out after by which optimized solid dispersion were kept in an oven at a temperature of 40^oC±1^oC and a relative humidity of 75%. The release profiles and drug content of the solid dispersion were determined at the end of 1, 2, 3 and 6 months, respectively, and compared with that of freshly prepared solid dispersion.

Figure 5: HSM photomicrographs of GPZ powder, HPC, GPZ-PM and GPZ-CE.

RESULTS AND DISCUSSION:

State of solid dispersions:

XRD and DSC curves of GPZ powder, the physical mixture prepared with HPC-SL and solid dispersions are shown in Fig. 1 and Fig. 2 respectively. In solid dispersions and the physical mixture, XRD spectra and melting endothermic peak of GPZ around 209⁰C was not observed in Fig. 1 and Fig. 2 respectively. The other three physical mixtures prepared with different grades of HPC showed the same results as GPZ-PM and GPZ-CE (data not shown). These results suggest that GPZ existed in the amorphous state in the solid dispersion, and that a slight amount of GPZ was contained in the solid dispersion. For GPZ, IR stretching bands are 3250.50 cm^-1 (N-H stretching), 2935.0 cm^-1 (C-H stretching of methylene group), 1689.0

cm^-1 (C=O), 1650.0 cm^-1 (-CONH-), 1445.0 cm^-1 (substituted cyclohexane), 1160.0 cm^-1 (sulphate group) and 610.0 cm^-1 (disubstituted benzene) was still visible in physical mixture suggesting that there was no interaction between drug and polymers, while carbonyl group totally disappeared in corresponding solid dispersions (Fig. 3) resulting in a broad band as well as altered stretching and bending vibrations. This result suggested the possibility of intermolecular hydrogen bonding between GPZ and HPC-SL in solid dispersions. These interactions were made while the molecules were in solution that is when the distances between the molecules were so small that association between functional groups is possible. SEM images for pure drug, pure HPC, physical mixture and solid dispersion of HPC-SL are shown in Fig. 4.

Table 2. Stability of optimized solid dispersion system under accelerating conditions

Time (month)	%drug * content	% drug released*
Time (month)	%drug * content	2h	4h	8h	12h	24h
0	98.82± 0.005	37.58±0.005	42.43±0.005	56.06±0.002	83.02±0.006	90.89±0.005
1	90.36± 0.009	30.09±0.002	38.20±0.007	52.04±0.009	81.21±0.009	90.53±0.004
2	89.55± 0.008	28.28±0.008	33.99±0.006	47.83±0.008	78.50±0.003	88.12±0.002
6	87.97±0.007	28.58±0.009	33.09±0.004	46.33±0.004	76.69±0.001	89.03±0.003

* Study was performed on three replicates

Pure drug image showed crystalline drug of irregular shapes and sizes whereas in physical mixture, the HPC existed as individual particles with GPZ dispersed in its native crystalline form. Solid dispersion was quite distinct from the physical mixture as it was not possible to identify drug and polymer as separate entities and they seemed to have lost their original crystallographic habits. As opposed to the physical mixture, these particulates displayed much larger, rougher and spherical surfaces, presumably from GPZ crystals incorporated into the swelled polymer. Fig. 5 showed that at 129⁰C pure drug was completely melt however pure HPC at 75⁰C showed complete melting of particles (Fig. 5). In the solid dispersion, we observed the birefringence of drug in the molten carrier. After heating up to 75˚C GPZ was easily recognized as tiny particles dispersed throughout the molten carrier. Physical mixture showed more birefringence as compared with respective solid dispersions. The complete dissolution of drug in polymer occurred at 122.40˚C. These result confirmed the disappearance of GPZ melting endothermic in the DSC thermogram of physical mixture and solid dispersions were attributable to dissolution of the drug into the molten carrier.

Figure 7: Effects of Molecular Weight of HPC on Release Rate of GPZ from Solid dispersion granules. Each point represent the mean ± S.D. (n=3).

Effects of the granule size of solid dispersion on the dissolution behavior of gpz:

Fig. 6 showed the release profiles from different sizes of solid dispersion granules prepared with different molecular weights of HPC and different sizes of GPZ powder. The release rate of GPZ from each solid dispersion granule was larger than that from any GPZ powder. The release rate increased with a smaller granule size in every solid dispersion granule prepared with four different molecular weights of HPC. It was thought that the reduction in granule size caused an increase in the effective surface area of the granule for the dissolution of GPZ.

Effects of molecular weight of HPC on the release rate of GPZ from solid dispersion granules

The effects of the molecular weights of HPC on the release rate of GPZ from solid dispersion granules are showed in Fig. 7. In all the solid dispersion granules, high release rates were observed compared with that from GPZ powder. The release rate of GPZ from solid dispersion granules increased with the smaller molecular weight of HPC. It was thought that these results were caused by the difference in the solubility of HPC in the dissolution medium and the diffusion rates of GPZ in the swelled phase HPC.

Effects of pH on release rate:

Fig. 8 shows the effect of the dissolution medium on the release rate of GPZ. In both cases of GPZ powder and solid dispersion granules, the release rates increased with a higher pH of the dissolution medium. The release rate of GPZ from solid dispersion granules was larger than that from GPZ powder in a wide range of pH. Particularly, in the range of 1-8, which is the pH in digestive tract, a significant improvement was observed in the solubility of GPZ. These results suggest that the bioavailability of GPZ may be improved by using the solid dispersion method.

Stability Studies:

From the data (Table 2) it was concluded that after 1, 2, 3 and 6 month at 40^oC±1^oC no change in physical appearance was observed. Drug content and dissolution of GPZ was almost similar to that at time zero during the whole period of investigation. The improved stability of solid dispersion could be due to the hydrogen bonding in between the drug and the HPC. It was indicated that excipients contributed towards protecting the dispersion state of the drug.

CONCLUSION:

Extended release of solid dispersion of water insoluble GPZ was successively prepared by coevaporation with different grades of HPC. The sustainment of drug release was effected by granule size of solid dispersion, molecular weight of polymer and pH of the medium. The analysis by spectral technique FT-IR suggested possibility of hydrogen bonding. The results of DSC, XRD and SEM studies revealed the reduction in crystallinity of pure drug in solid dispersions as compared to their physical mixtures. Dissolution behavior suggested that release rate of GPZ from solid dispersions increased with a higher pH. The studies indicated that coevaporate of water insoluble GPZ with lower molecular weight HPC can be prepared and extend release up to 12 hrs.

Figure 8 Effects of pH on Release Rate of GPZ from Solid dispersion Granules and GPZ powder. Each point represent the mean ± S.D. (n=3).

ACKNOWLEDGMENTS:

Thanks are due to Prof. Awani K. Rai and Prof. Brijendra Srivastava at Pranveer Singh Institute of Technology and Jaipur National University for financial support. Central Drug Research Institute and Indian Institute of Technology are gratefully acknowledged for analytical studies.

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