INTRODUCTION:

Most of the active pharmaceutical ingredients are synthesized by using new synthesis process. Application of new synthesis techniques for synthesis of active pharmaceutical ingredients results low bio-available and less aqueous soluble drugs. Improvement of aqueous solubility and dissolution rate of these molecules is not easy task. Various methods are used for enhancement of aqueous solubility of these active pharmaceutical ingredients. Solid dispersion, on the other hand, is the most promising strategy for increasing solubility and dissolving rate.¹

The dissolution rate was reported to be increased after the formulation of solid dispersion due to the factors which are i) the reduction of the drug particle size to molecular level, (ii) the solubilizing effect on the drug by the water-soluble carrier, and (iii) the carrier material's enhancement of the drug's wettability and dispersibility.^2-4According to Biswal et al, 2008; another factor such as changes in molecular level of drugs from crystalline to amorphous improves dissolution rate.^5,6Gupta et al, 2009 reported enhanced bio-availability of glipizide by using a polymeric mixture of ethyl cellulose and hydroxypropyle methyl cellulose.^7,8 Solid dispersion of nifedipine with hydroxypropyl methyl cellulose and eudragit polymers, improved bio-availability.⁹

Many different carriers have been found to increase the solubility and bioavailability of poorly water-soluble drugs, including polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, gelucires, eudragits, and chitosans.^10-21But, it has been reported by Kohri et al., 1999 and Kushida et al, 2002, that hydroxypropyl methylcellulose is considered as most suitable carriers for preparation of solid dispersion as compared to other water soluble carriers due to its enhancement of water solubility and presentation of recrystallization in dissolution medium of drugs.^22-29

It present study, physicochemical properties of glipizide, a BCS class II drug, solid dispersion with HPMC were assessed using Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC). The phase solubility analysis and dissolution test were used to investigate the interaction in solution. In vivo study of solid dispersion in rat was also investigated. Subsequently, bioavailability of pure glipizide, solid dispersion and marketed product was performed.

MATERIALS AND METHODS:

Materials:

M/s Micro Laboratories Ltd, Bangalore, India provided a glipizide sample as a gift. Throughout the study, double distilled water was used, and all other compounds were of analytical quality.

Preparation of SDs:

The SDs of glipizide with HPMCLV comprising three distinct weight ratios (1:1, 1:2, and 1:5) (Glipizide: HPMCLV) were made using the solvent evaporation method and are denoted as HSD1/1, HSD1/2, and HSD 1/5, respectively.¹⁷In a mortar, the needed amount of glipizide and HPMCLV were thoroughly mixed for 10 minutes to produce physical mixtures (PMs) with the same weight ratio as SDs. The resulting mixes were sieved through a 100-mesh sieve and are denoted as HPM 1/1, HPM 1/2, and HPM 1/5. The mixes were kept at room temperature in a screw-cap vial until they were used.

Solubility Determinations of Glipizide:

Solubility determinations were performed in triplicate according to the method of Higuchi and Connors.³⁰

Dissolution Studies:

Dissolution tests of glipizide in powder, SDs, and PMs were carried out in 900mL 0.1N HCl containing 0.25 percent (w/v) of SLS as a dissolution medium using the USP model digital tablet dissolution test apparatus-2 (Veego Scientific Co.) at a paddle rotation speed of 50 rpm. at 37±0.5^ºC.³¹ A digital balance (Ohaus Corp) was used to weigh the SDs or PMs equivalent to 10mg of glipizide, which were then added to the dissolution medium. 10mL samples were removed using a syringe filter (0.45m) (Sepyrane, Mumbai) at the indicated periods (every 10 minutes for 2 hours) and then analysed for glipizide content using a UV-Visible spectrophotometer at 227nm (Shimadzu 1601PC, Japan). After each sampling, fresh medium (10mL) was added to the dissolution medium, which was pre warmed at 37^oC to keep the volume constant throughout the test.

Fourier-Transform Infrared Spectroscopy:

Fourier-transform infrared (FT-IR) spectrometer-430, Jasco Japan, was used to obtain FT-IR spectra. The samples (Glipizide, SDs, or PMs) were pulverised and thoroughly mixed with potassium bromide, an infrared transparent matrix, at a ratio of 1:5 (Sample: KBr). The KBr discs were made by compressing particles in a hydraulic press at a pressure of 5 tons for 5 minutes. From 4600 to 300cm^-1, forty scans were acquired at a resolution of 4 cm^-1.

Differential Scanning Calorimetry:

A DSC-6100 differential scanning calorimeter with a thermal analyzer (Seiko Instruments, Japan) was used for the DSC study. All correctly weighed samples (about 1.675mg of Glipizide or its equivalent) were placed in covered aluminum pans and heated in a scanning oven under nitrogen flow (20ml/min) rate of 10˚C min^-1 from 25˚C to 250˚C. As a standard, an empty aluminum pan was used.

X-Ray Diffraction:

At ambient temperature, the X-ray powder diffraction patterns were acquired using a PW1710 X-ray Diffractometer (Philips, Holland) with Cu as anode material and graphite monochromatic, operated at 35 kV, current 20mA. The samples were evaluated in a two-angle range of 5–70 degrees, with the following process parameters: scan step size of 0.02 (2), scan step length of 0.5 seconds.

Assessment of Therapeutic Efficacy:

These tests were carried out on free drug, HSD1/2 and the marketed drug product, which were chosen based on results from dissolution studies. (Glynase, B. No. 13014685, USV Private Ltd, India). Using diabetic rats, this study used a single dose and a parallel group approach. Male Wistar rats weighing 180–240g was fed a regular diet for 10–14 days before being given an intraperitoneal injection of 50mg/kg streptozotocin to induce diabetes.^32,33Three groups of three rats were formed from these rats. The Fast Take Glucometer (SmartScan®) was used to measure fasting blood glucose levels. The blood glucose level (BGL) was evaluated at various time intervals up to 24 hours following intragastric tube administration of a single dose of 25mg/kg of the pure drug or its equivalent amount of solid dispersion or marketed product. The animal's blood was taken from its orbital sinus. Because each animal served as its own control, the hypoglycemic reaction was measured as a percentage decrease in blood

glucose level: (1)

BLG AT T = 0 – BLG AT T

% Decrease in blg = ------------------------------- X100

BLG at t = 0

The highest percentage reduction in blood glucose level (Emax), time for maximum response (tmax), and area under the percentage decrease in BGL versus time curve (AUC0–24h), which were determined using the trapezoidal rule, were the pharmacodynamic parameters considered.³⁴

RESULTS AND DISCUSSION:

Solubility Studies:

The presence of HPMCLV has a significant impact on the concentration of glipizide in aqueous, according to solubility studies (table 1).In a concentration range of HPMCLV (2-4 percent w/v), the phase-solubility diagram studied aqueous was linear and corresponded to AL-type profiles.³⁰ The stability constant was found to be 0.0428 ml^-1mg. Increased solubility may be due to the improved dissolution of glipizide particles in aqueous solution by HPMCLV. At 4% (w/v) concentration of HPMCLV, the solubility of glipizide increased by 1.146-fold (table 1). Table 1 presents the values of Gibbs free energy associated with the aqueous solubility of glipizide in presence of HPMCLV. ΔG_tr^ovalues were all negative for HPMC at various concentrations indicating the spontaneous nature of HPMCLV increased.

Dissolution Studies:

The results of the dissolution studies for individual samples (glipizide alone, PMs and SDs) over the period of 1 hour are given in table 2 and reported values are the mean three determinations (CV<10%). Q₁₀, Q₂₀ and Q₃₀ values (percent drug dissolved within 10, 20 and 30 minutes) with HPMC are reported in Table 2. From the table 2, it is evident that the onset of dissolution of pure glipizide is very low, about 18.46% of drug being dissolved within 10 min (Q₁₀). HSDs of glipizide with HPMCLV considerably enhanced dissolution rates within 30 min compared to pure glipizide and HPMs (Table 2, Q₁₀, Q₂₀ and Q₃₀). The value of % DE_10minfor pure glipizide (9.16%) was enhanced in HPMs (14.5%) as well as in HSDs (22.86%). The value of % DE_30min for the pure drug was increased to 30.5% in HPMs and up to 40.81% in HSDs (table 2). The mechanism for how the solid dispersions process yields enhanced dissolution properties is believed to be a microenvironment surfactant effect whereby HPMC dissolution creates a local surfactant concentration in the boundary layer surrounding the drug particles, providing a lower energy pathway for drug dissolution.³⁵ From Table 2, MDT of glipizide is 12.5 min, it decreased to 7.24 min in HSD with HPMCLV at 1:5 (glipizide: HPMCLV) ratio.

Table 1: Effect of HPMCLV concentration and Gibbs free energy on solubility Glipizide

Concentration of HPMC LV %w/v)	Concentration of Glipizide(mg/ml) at 37 °C	ΔG_tr^o(J/Mol)
2.0	0.81±0.001	-51.03
2.5	0.83±0.003	-67.48
3.0	0.88±0.002	-218.27
3.5	0.91±0.001	-304.73
4.0	0.94±0.002	-388.15

(The experiments were repeated in triplicate, n=3)

Table 2: In-vitro dissolution profile of Glipizide, physical mixture of Glipizide and solid dispersion of Glipizide with HPMC LV in 0.1NHCl (pH 1.2)

Formulations	Dissolution parameters
Formulations	Q_10min	Q_20min	Q_30min	%DE_10min	%DE_30min	MDT (min)
Glipizide	18.46±0.8	32.67±2.4	40.82±2.9	9.16±0.9	23.67±1.2	12.5±0.8
HPM1/1	19.5±1.4	35.6±1.6	44.5±3.1	10.5±1.5	25.6±1.5	11.5±0.5
HPM1/2	22.5±1.8	38.5±2.1	46.6±1.6	13.5±1.4	27.5±1.8	10.5±1.1
HPM1/5	26.5±2.3	42.5±1.8	50.5±2.3	14.5±1.9	30.5±2.4	8.5±1.3
HSD1/1	40.9±1.3	41.6±1.1	45.2±1.3	20.47±2.4	35.04±1.3	6.75±0.7
HSD1/2	42.2±2.2	44.4±2.7	46.3±1.7	21.10±2.1	36.58±1.8	6.28±1.1
HSD1/5	45.7±1.5	49.8±1.9	53.8±1.9	22.86±2.8	40.81±3.2	7.24±0.7

*HPM: Physical mixture with HPMC, HSD: Solid dispersion of Glipizide with HPMCLV prepared by solvent method_.

FTIR-Spectroscopy:

FTIR spectroscopy was used to characterize the possible interactions between drug and carrier in the solid state. The IR spectra of HSD and HPM were compared with the standard spectrum of glipizide (Fig 1D, 1C, and 1A). In spectra of HSDs and HPMs, carbonyl (C=O) this band was shifted towards higher frequencies at 1735 cm^-1 and 1715 cm^-1 respectively (Fig.1C and 1D). Also, the NH group which is located at 3265 cm^-1 from the IR spectrum of glipizide shifted to 3365 cm^-1 in HSDs. The sulphonyl group bands are located at 1349 cm^-1 and 1162 cm^-1 in pure glipizide. In HSDs, the asymmetrically vibration peak of S=0 band was shifted from 1349 cm^-1 to 1339 cm^-1 with decreased frequencies. In HSDs, the symmetrically stretching vibration band of S=0 was shifted from 1162 cm^-1 to 1167 cm^-1 with decreased frequencies. The shift in the peaks associated with sulfonylurea group of the glipizide indicate an increase in bond strength possibly due to stabilizing effect of the hydrogen atoms of HPMC interacting with the oxygen atoms of the sulphonyl group.It could be expected to have hydrogen bonding between the hydrogen atom of the NH group of glipizide and one of the ion pairs of oxygen atom in the HPMCLV.

Fig 1: FTIR Spectrograms of pure Drug(A), Pure HPMCLV (B), Glipizide -HPMC PM at 1:2 ratio, (C), Glipizide -HPMCLV SD at 1:2 ratio(D)

X-Ray Diffractions (XRD):

The diffraction spectrum of pure glipizide showed that the drug was of crystalline nature as demonstrated by numerous peaks. Numerous diffraction peaks of glipizide were observed at 2θ of 10.59, 14.98, 17.2, 17.85, 18.15, 22.07, 25.42, 26.25, 26.75 and 29.5 (finger print region) etc. (Fig 2A) indicating crystalline glipizide. Pure HPMCLV showed no peaks hence amorphous in nature (Fig 2B). Some changes in peaks position of glipizide were observed in HPMs as well as HSDs (Fig 2C and Fig 2D). The prominent peaks from pure glipizide observed at 2θ of 10.59, 14.98, 17.1, 18.15 and 22.07 were not observed clearly seen at the same position in the HPMs and in HSDs. From, the aforesaid observations it is concluded that the crystalline nature of that drug was not maintained. The positions of peak patterns in the HPMs and HSDs were not same, which again indicates the possibility of chemical interaction and new compound formation between these two components and/ or indicates conversion of drug from crystalline to amorphous form.

Fig 2: X-Ray Diffractograms of pure Drug(A), HPMC (B), Glipizide-HPMC PM at 1:2 ratio (C), Glipizide-HPMCLV SD at 1:2 ratio (D).

Differential Scanning Calorimetry:

The DSC curve of pure Glipizide exhibited a single endotherm corresponding to the melting of the drug. The onset of melting was observed at 170.8 °C, and the corresponding heat of fusion (ΔH_F) was 171.8 J/g (Fig 3A), whereas pure HPMC showed a broad endothermic melting peak (Fig 3B). Thermograms of HSD (Fig 3D) showed the absence of a glipizide melting peak. This indicates conversion of drug from crystalline to amorphous form. The HPM formulation of glipizide and HPMCLV also showed an endothermic melting peak at 165.35˚C (Fig 3C). It is speculated that glipizide remains in crystalline form in HPM.

Fig 3: DSC thermograms of pure Drug, (A) HPMCLV (B), Glipizide -HPMCLV HPM at 1:2 ratio (C), Glipizide -HPMCLV HSD at 1:2 ratio (D)

Assessment of Therapeutic Efficacy:

The mean percentage decrease in BGL of diabetic rats after administration of HSD1/2, and the marketed product was computed and the data are given in Table 3. It is evident that the percentage decrease in BGL–time profiles for the investigated systems are quite different. The percentage decrease in BGL, 12h and 24h post administration, of the HSD1/2 is higher (p<0.001) than the corresponding values of the marketed drug product. This indicates that the duration of action of the suggested formula is markedly longer than that of the marketed drug product.

With respect to the time for maximum percentage decrease in BGL (t_max), it is evident from Table 3 that t_max of the HSD1/2 has the lowest value, but the free drug and the marketed drug product have similar t_max value. This would indicate that the HSD1/2 exhibits a faster onset of action compared to that of the marketed product. The difference between the value of t_max of the HSD1/2 and that of the marketed product is very highly significant. On the other hand, the difference between the value of t_max of the HSD1/2 and that of the free drug is significant. There is no difference between the t_max value of the marketed drug product and that of the free drug.

Table 3 shows that the values of E_maxfor the HSD1/2 and the marketed formula are not similar and much higher than that of the free drug. Statistical analysis indicates that there is significant difference between the value of E_max of the HSD1/2 and that of the marketed product. On the other hand, there is a high significant difference between the E_max of the marketed drug product or the HSD1/2 and that of the free drug. This would indicate that both the HSD1/2 and the marketed product have a pronounced longer duration of action compared to that of the drug.

Regarding the area under the percentage decrease in BGL–time curve (AUC_{0–24 h}), it is evident that the HSD1/2 has the highest value followed by the marketed drug product and then the free drug (Table 3). The difference between the AUC-value for the HSD1/2 and that of the free drug is very highly significant, while the difference between the AUC-value for the HSD1/2 and that of the marketed drug product is significant. This would indicate that the HSD1/2 formula shows a better therapeutic efficacy compared to that of the free drug or the marketed drug one. The HPMCLV shows surfactant activity which is responsible for better (AUC_{0–24 h}).

Table 3: The pharmacodymamic parameters of free drug, HSD1/2, and marketed formulation

Formulations	t_max(h)	E_max(%)	AUC_0-24h
Free drug	8	42.5±4.23	535.65±11.5
HSD 1/2	4	62.64±5.14	1017.19±25.63
Marketed formulation	8	50.2±4.56	767.5±13.60

CONCLUSIONS:

The solid dispersion of glipizide with HPMCLV was prepared using solvent evaporation method. The solid dispersions were characterized by using FTIR, XRD and DSC. The drug release study was performed using dissolution test. The solid dispersion of glipizide with HPMCLV at 1:2 was selected for in vivo study. The solubility and dissolution rate of glipizide was enhanced by the use of SDs of Glipizide with HPMC. The solubilization effect of HPMC in SDs and PMs due to reduction of particle aggregation of the drug, absence of crystallinity, increased wettability and dispersibility and alteration of the surface properties of the drug particles. The absence of an endothermic peak of glipizide in the DSC thermograms of SDs with HPMCLV showed the conversion of glipizide from crystalline to amorphous state. From FTIR spectroscopy, it was concluded that there was no well-defined chemical interaction between glipizide and HPMCLV, since no important new peaks could be observed. The solid dispersion of glipizide with HPMCLV (1017.19±25.63) showed better therapeutic activity compared to pure glipizide (535.65±11.5) and marketed formulation (767.5±13.6). It is concluded that the SDs of glipizide with HPMCLV provide a promising way to enhance its solubility, dissolution rate and bio-availability.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 03.11.2021 Modified on 01.12.2021

Research J. Pharm. and Tech 2023; 16(2):555-560.

DOI: 10.52711/0974-360X.2023.00095