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JSM Diabetology and Management

Solid Dispersion Techniques for enhancing Dissolution and Bioavailability of lipophilc antidiabetic agent glimepiride by Alkalizers

Research Article | Open Access Volume 4 | Issue 1 |

  • 1. Assistant Professor, Department of Biochemistry, Government College Women University, Faisalabad, Pakistan
  • 2. PhD Scholar, Department of Pharmaceutics, Government College University, Faisalabad, Pakistan
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Corresponding Authors
Naila Abdul Sattar, Assistant Professor, Department of Biochemistry, Government College Women University, Faisalabad,
Abstract

Aim: Objective of the present study to enhance the dissolution bioavailability of antidiabetic agent of class III sulfonyurea Glimepiride (GM) through synthesis of ternary solid dispersion (TSD) through alkalizers.

Materials and methods: GM and TSD were synthesized by hot melt extrusion (HME) along Kollidon® VA64 using as carrier compound while Lysine/meglumine as alkalizer agents. The release of ternary solid dispersion in vitro was evaluating by dissolution and dissociation constant (pKa). Morphological study of the resultant modified drug observed by scanning electron microscopy (SEM), different scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) while kinetic study done by X-ray photoelectron spectroscopy(XPS), fourier transform infrared spectroscopy (FTIR), raman Spectroscopy (RS) and molecular docking.

Results: Dissolution of GM notably elevated of TSD in comparison to pure GM and binary solid dispersion turned into amorphous shape with high ionic paired energy in TSD. TSD lower pKa value expresses that greater degree of ionization is good for dissolution of the GM.

Conclusion: Modified forms of alkalizers proved beneficial in improving the dissolution of GM and exhibited a good potential in delivery systems of drug

Keywords


•    Poorly water-soluble drug
•    Solid dispersion
•    Alkalizers
•    Glimepiride
•    Molecular interactions
•    Dissolution

Citation

Sattar NA, Ibrahim HM (2021) Solid Dispersion Techniques for enhancing Dissolution and Bioavailability of lipophilc anti-diabetic agent glimepiride by Alkalizers. JSM Diabetol Manag 4(1): 1006.

INTRODUCTION

Hyperglycemia or diabetes is metabolic disorder that attaining wide attention globally. Various oral antidiabetic agents are rapidly growing to fulfill the needs of diabetic people [1,2]. Glimepiride (GM) is one of most suitable antidiabetic drug for the management of type 2 diabetes mellitus (T2DM) by directly acting on beta pancreatic cells and activate the secretion of insulin [3,4,5]. Glimepiride has high protein binding with long acting and permitting for associated employ with insulin, but drawback of using GM as oral dose attributable of its little aqueous solubility (1.3µg/mL) with slow dissolution rate that lead to poor oral bioavailability [6,7]. Different studies have conducted to increase its solubility by using spray congealing, [10], solid dispersions, [12], solid self-nanoemulsify, [11] and micelles, [13]inclusion complexation [14,15]with limited success [16-18]. HME technology has been extensively adopted due to its continuous control in limited time requiring; solvent free. [21]. SD polymers stabilizes the amorphous powder form of GM and protect re-crystallization [22,23], limited capacity of solubilization to binary solid dispersion along pH dependent GM. McFall [24] observed that dissolution and bioavailability of drug may improve by succinic acid (acidifier). Tran [25] described that sodium bicarbonate act an alkalizer to maintain pH micro-environment, increased the rate of dissolution of weak acidic drug like aceclofenac in SD. Choi [26] verified that rate of dissolution by increase solubility in vitro may increase bioavailability in oral route. Sun [27] developed pH M-SD of Toltrazuril along Ca(OH)2 as alkalizer. However, mostly studies focused exclusively on acidifiers on weak alkaline drugs. There are few studies on using alkalizers to improve the solubility of weakly acidic drugs. Main bioactive component of GM, (Figure 1), has been found as antidiabetic pharmacological characteristics [28-30], poorly insoluble in water with pH dependent solubility. According to various studies, BSDs make hard to increase the dissolution of GM efficiently. The purpose of present study was to develop a SD model with assimilation of alkalizers to increase solubility and dissolution in vitro. Moreover, examine the modulating procedure of alkalizers in SD model. TSDs of GM were formed by HME. Solubility in water and dissolution were estimated for the active drug and TSD, pKa described the degree of ionization of GM in different pH. Raman, SEM, XPRD, DSC, XPS, FTIR and a molecular docking were worn to carry out the solid state characterizations, dissolution mechanism for TSDs.

MATERIALS AND METHODS

Following materials were taken from commercial suppliers; CaCO3 , Na2 CO3 , Mg(OH)2 , NaOH, Na2 HPO4 , and MgO and Polyvinylpyrrolidone, Polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), poloxamer 407, and poloxamer 188, L-lysine (LA), Meglumine (MG) was purchased from Tian Run Pharmaceutical Co, Ltd. (Guangzhou, China), Glimepiride (GM) GRN# 21080030, Batch#84200671 Glenmark life sciences Ltd, affinisol, ethyl cellulose (EC) , hydroxypropyl methyl cellulose (HPMC) and hydrochloric acid were purchased McCann Chemicals, Kings Road, Immingham DN40 2DW, (Birmingham,UK).

Solubility of Alkalizers and Polymers

Both polymers and alkalizers mention above were screened as suitable for SD. Take 500mg of alkalizers or polymers in centrifuge tube consisting 50mL of different media having pH 1.5, pH 4.5, pH 6.8 and pH 8.0 to get 1% aqueous solution. Suitable amount of GM was taken into centrifuge tube that contains each aqueous solution. Vortex the aqueous solution to get proper mixed solution then kept it in shaking water bath revolving at 80rpm for 70h at 37ºC. Centrifuged the above solution for 15 minutes at 8000rpm having temperature 25ºC to isolate non soluble GM. Filtered the supernatant through 0.45µm aqueous filter, then dilute it with buffer of corresponding pH. Quantified the GM by UV-Vis spectrophotometer (UV-1750, Shimadzu, Suzhou, China) and note absorbance at 225nm. Triplicates were used of every test.

Preparation of Solid Dispersion

The sodium bicarbonate, Mg(OH)2, L-arginie /lysine and meglumine were chosen as alkalizers while Kollidon® VA64 as hydrophilic SD carrier was chosen. Selected excipients were sieved via 80-mesh sized strainer and kept in vacuum oven made by Biorad UK for 15 hours at 50?C to get rid of extra water. All ingredients were mixed thoroughly by tri dimensional mixer (Biorad UK), then samples were prepared through 20mm biscrew HME Biorad UK at 170?C and 100rpm. Extrudate was cooled down to 37?C, pulverizer until a fine powder formed that could pass by 200 mesh sized sieve, stored in a amber color glass jar for next more analysis. In tables 1 and 2 showing formulations of HME, while mixtures of same ratios were prepared and stored in desiccators to avoid hygroscopicity.

Dissolution of SDs

Glimepiride dissolution was studied for the above formulations at ambient temperature ± 0.5 ?C and 90rpm, paddle apparatus (ERWEKA USA Inc.), according to British pharmacopoeia (2015). The buffer (900mL) of pH 1.5-6 added in each vessel of dissolution apparatus as medium. Filtered take 10mL from each vessel for 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes with corresponding 10mL fresh medium were taken for compensation. Samples were analyzed spectrophotometrically at 225nm using biorad spectrophotometer.

Characterization of Optimal Formulation

From results of dissolution test, F2, F14, and F18 were taken as optimized composition of formulation with good GM release (curve) as compared with API of GM and other formulations.

Estimation of Dissociation Constant (pKa)

Calculate pKa value of GM by spectrophotometry according to the principle; molecular and ionic phase of a compound show different absorption for specific wavelength of light [31-33]. On equilibrium of dissociation of a compound, both molecular and as well as ionic phases are found which shows different absorptions of light at same wavelength. GM, meglumine, BSD, ternary solid dispersion (MG-TSD) and Lysine TSD (K-TSD) samples of same concentrations were selected to synthesize three solutions for analysis respectively. Such samples may exist with different dissociation phases by adjusting pH.

Absorbance (Ax , AHM, and AM−) was taken with an UV spectrophotometer at 225nm while its pKa was calculated by expression as follows

pKa = pH + lg Ax-AM- / AHM-Ax (1)

Where AM- represent absorbance of 100% ionic phase of the solution, AHM is absorbance of molecular phase of same 100% and Ax represent absorbance of whole solution of compound.

Scanning Electron Microscopy (SEM)

Samples were sputter coated with gold thin layer to analyze for their surface morphology by SEM (BioCompare, UK).

Different Scanning Calorimetry (DSC)

The 2-5mg samples were kept in standard aluminium pan through vent cap and sealed of DSC (BioCompare, UK) for thermodynamic study. Start heating with rate of 2?C/minutes and rise up to 45?C to 370?C to get curve through purging with flow rate of 40mL/minutes in dynamic nitrogen atmosphere.

X-ray Powder Diffraction (XRPD)

The pattern of XPRD for polymer was obtained by using Bruker D8 diffractometer (D8 Advance, Bruker AXS, Karlsruhe, Germany) and analyzed crystal state of GM, operated via copper anode tube with 40 kV generator voltage and 40 mA current respectively. Scan range 3-theta was adjusted from 10? to 65? with flow rate 0.05?/minutes and analyzed data by OriginPro 8 software.

Fourier Transform Infrared Spectroscopy (FTIR)

To interpret molecular data of GM FTIR (Bruker Vertex 70 spectrometer, Kennewick, WA, USA) spectra required. Dissolved samples in EA through KBr coating and dropped as particles, dried for 10minutes at 55?C to get rid from EA. Relative spectra were obtained through scanning 125 times in the spectral range of 4000-400 cm-1. Analysis and De-convolution were done by using OriginPro 7 (OriginLab, Northampton, MA, USA).

Raman Spectroscopy (RS)

Following analysis employed as complement to Fourier Transform Infrared Spectroscopy for direct analyzing of molecular data of interaction between GM and the alkalizers. RS was noted on a Renishaw (Renishaw, London, UK) in via laser micro-RS with 785nm of 300mW. Samples were kept on aluminum plate having 50X objective lens for 20second (acquisition time) with range of 3500-200 cm-1 of spectrum. Data was analyzed by using WiRE software (Wire Swiss, Zug, Switzerland) before deconvolution and PeakFit 4.0 software (Systat Software, San Jose, CA, USA) after deconvolution of peak.

X-ray Photoelectron Spectroscopy (XPS)

Protonation phase of GM-MG, MG-TSD/LA-TSD, GM-MG/ GA-LA and GM-LA in SD was examined by X-ray Photoelectron Spectroscopy (Thermo Fisher Scientific, Waltham, MA, USA) equipped with monochromatic aluminum and Kα X-ray. The XPSPEAK 41 peak-fitting software used to analyze the data.

Molecular Modeling

The confirmation of RS, XPS and FTIR has been done by molecular modeling. Crystal particles of GM and excipients were taken from CCDC (Cambridge Crystal Data Centre) with deposition#: Glimepiride (19199390), L-lysine/lysine (179326) and meglumine (2336196) acid Materials Studio 2017 (Accelrys, San Diego, CA, USA) was taken for MD while, intermolecular interactions were examined by COMPASS force field.

Molecular Docking (MD)

Geometrical optimization was done by forcite module, perform MD with Blends module. Select the good docking type on the basis of binding energy score.

Optimized formulation for solubility and dissolution

Extra concentrations of extrudates were taken in 15mL volumetric centrifuge tubes to analyzed solubility of different media of pH 1.5, 5.0, 6.5 and 7.5. Vortex them and kept in shaking water bath with speed 75rpm for 75hours at ambient temperature, then centrifuged speed 8000rpm at 25?C for 20 minutes and take supernatant. Filtered the supernatant via 0.45µm filter and dilute with reference of buffer. Noted the absorbance at 225nm Study of dissolution was done by SOTAX dissolution. Samples of LA-TSD, API, MG-TSD and BSD were kept in 900mL solutions of different buffers at ambient temperature ± 0.5?C in paddle apparatus with 80rpm speed to find GM release. Media compensation was done as describe previously after drawing samples of volume 10mL at in following intervals of time; 5, 10, 15, 20, 30, 45, and 60 minutes. Note the absorbance at 225nm.

Table 1: Formulation of SD (F1–F12).

  GM (g) pH Modifier                                        Kollidon® VA64 (g) Ratio Total (g)
    Mg(OH)2 (g) Na2CO3 (g)    
F1 6 - -76 1:0:15 82
F2 9 - -73 1:0:9 82
F3 17 - -65 1:0:4 82
F4 33 - -49 2:0:3 82
F5 7 7 -49 1:1:8 63
F6 7 13 -49 1:2:7  
F7 7 19 -37 1:3:6 63
F8 13 19 -31 2:3:5 63
F9 7 - 7    49 1:1:8 63
F10 7 - 13  43 1:2:7 63
F11 7 - 19  37 1:3:6 63
F12 13 - 19  31 2:3:5 63

Table 2: Formulation of SD (F13–F20).

Formulation GM (g) pH modiifier Kollidon® VA64 
(g)
Ratio Total (g)
Meglumine (g) L-lysine(g)
F13 7 7 - 49 1:01:08 63
F14 7 13 - 43 1:02:07 63
F15 7 19 - 37 1:03:06 63
F16 13 19 - 31 2:03:05 63
F17 7 - 7 49 1:01:08 63
F18 7 - 13 43 1:02:07 63
F19 7 - 19 37 1:03:06 63
F20 13 - 19 31 2:03:05 63

Table 3: pKa values of GM, BSD, MG-TSD, LA-TSD.

NO. pH GM BSD MG-TSD LA-TSD
1 6.5 7.17 7.02 6.42 6.72
2 7.0 7.18 7.01 6.44 6.73
3 7.5 7.17 7.07 6.44 6.71
4 8.0 7.16 7.09 6.43 6.73
Average value of pKa   7.17 7.05 6.43 6.72

 

RESULTS AND DISCUSSION

Solubility Screening

Selected polymers and alkalizers were screened for solubility and dissolution of GM. Results revealed GM show no any interaction with excipients, alkalizers and polymers at 225nm in HCl (pH 1.5) 5.0, 6.5 and 7.5 buffers (Figure 2a), greater solubility of GM-API noted in Kollidon® VA64, that elevated significantly in strong basic media of L-lysine/lysine, meglumine, Mg(OH)2 , and Na2 CO3 (Figure 2b).

Characterization Optimal Formulation 3

Dissociation Constant (pKa): By using Nernst-Noyes Whitney equation [34] elaborate the relationship between GM dissolution and GM saturation solubility.

dCb/dt = DS/Vh (Cs -Cb) (2)

where Cs is saturated solubility of GM on solid surface, Cb is amount of GM, h is thickness of diffusion layer, D is diffusion coefficient, S is surface area of solid, V represent volume of dissolution medium and t expresses time. Previous data expressed that degree of ionization of weak acidic drug exhibiting pH dependent and calculate by Henderson-Hasselbalch equation [35] for monoacidic material as follows

CS = CS01 + 10(pH−pKa) (3)

CS represents solubility of GM, CS0 is inherent solubility.

The pKa has central role in dissolution and solubility of ionogenic drugs (Table 3), dissociation constant of all samples was decreased as compared to API of GM, furthermore TSD showed lowest one values of pKa than BSD and API-GM, the MGTSD has lower pKa than LA-TSD. A small shift of in pKa value is responsible of high effects in the aqueous solubility of GM. drugs. The low pKa may increase Cs , to achieve supersaturated state lead to highest GM dissolution [36].

Scanning Electron Microscopy (SEM)

The GM-crystals (0.10-0.14mm3) are in Figure 4a, b, except large particles in SDs (Figure 4c-h). Data suggested that three types of GM raw materials were homogenously combined TSD, while surface of particles was roofed by Kollidon®VA [37,38].

Differential Scanning Calorimetry (DSC)

The DSC thermogram of GM, Kollidon® VA64 and their PMs/ SDs with and without alkalizers were shown in Figure 5. Curve of pure GM, LA, and MG have one endothermic peak at 300, 230, and 130?C, respectively with reference to intrinsic melting point of them. On contrast Kollidon® VA64 has no peak of melting point in DSC system. No peak of GM observed in SD while specific melting point peaks in SDs of MG and LA differ from molecular interaction exist among them [25]. Thus results demonstrated that TSD and BSD were non-crytalline/amorphous while GM has only 3% crystalnality in DSC system which cannot find out directly by DSC[27]. To overcome this situation PXRD was carried out for them.

X-ray Powder Diffraction (XRPD)

Following analysis was employed for the confirmation of amorphous form of BSD and TSD [38]. The results are of XPRD shown in figure 6. According to results GM was highly crystalline along LA and MG while Kollidon® VA64 shown wide peak with background pattern as revealed it is amorphous material. Polymers have characteristics to restrict the crystallite features with reduction in overall particle size to improve wettability [22,39,40]. Thus Kollidon® VA64 can be use to develop 100% amorphous features regardless of alkalizers (Lysine or meglumine). High rate of dissolution and solubility of class II drugs (BCS drugs) in amorphous SD may be developed through increasing porosity and wettability, decreasing particle size and finally prevented from recrystallization.

Fourier Transform Infrared Spectroscopy (FTIR)

Dissolution of drug depends upon various types of intermolecular forces including hydrogen bonding exhibit among atoms or ions [37,42], although ion-pair interaction is considerably due to opposite charge held through Coulomb force [43]. El Shaer used hydrophilic amino acids as counteract ions to lipophilic indomethacin, increasing its solubility and dissolution [44]. To find out intermolecular forces in SD FTIR used in present study, as in figure 7, peak of GM at 1725 cm-1 and 1660 cm-1 that indicating C=O interactions in carboxylic acid and ketone groups present in GM respectively. Although, peak at 3442 cm-1. Is of Kollidon® VA64 due to absorption of C3 consists two H-bond receptors i.e. C=O of pyrrolidone ring at 1668 cm-1 while at 1737 cm-1 vinyl acetate. Peaks of BSD and blank Kollidon® VA64 are similar that indicating no any prominent force found in GM and blank Kollidon® VA64. Other peaks are at 3339 cm-1 is of N-H belong to LA [45], at 3280 cm-1 of LA-VA extrudate, at 3330 cm-1 of secondary amine in MG [46] that misplaced from extrudate of MG-VA. Actual peak belong to Kollidon® VA64 is at 3481 cm-1 which shifted to 3423 cm-1 confirm the ionic hydrogen formation between alkalizers and Kollidon® VA64 [47-49]. Two major changes were noted spectra of LA-TSD as shown in figure 8c,d. At 3442 cm-1C 3 band of GM deleted by two peaks at 1571 cm-1 and 1375 cm-1, recognized asymmetric (Vas COO-) and symmetric (Vs COO-) vibrations of the carboxylic group [53] at 1566 cm-1 and 1359 cm-1 (Figure 8e,f), C3 band of GM misplaced from MG-TSD curve. Thus results revealed that ionic complexes produced by strong ionic forces exhibit in GM and alkalizers [45,54-59] that may be the reason of the improving dissolution of GM.

Raman spectroscopy

This technique used to confirm ion pair effect among substances here between GM and alkalizers. Results of raman spectroscopy shown in figure 9. In GM at at 970 cm-1 and at 846 and 898 cm-1 are stronger and weaker bands respectively, while at 1650, 1570, 1440, and 1160 cm-1 are of different deformation modes having N-H bond, similar to raman spectra of lysine at 1440 cm-1 [60]. K-VA64 extrudate appears at 1445 cm-1, secondary -NH of MG at 1480 cm-1 and at 1500 cm-1 of MG-VA64 extrudate. Dislocation of larger wave number reveals H-bond between Kollidon® VA64 and alkalizers. Thus for asymmetric and symmetric revolution peaks were appeared at 1415 cm1 , 1424 cm-1, 1681 cm-1, and 1687 cm-1 supported by previous studies [59-61]. Present results shown that ion pairs formed in alkalizers and GM deprotonated carboxyl group.

XPS

The XPS is sensitive tool used to study valence composition of substances [62]. In figure 10 the spectra is N1s of K-TSD, GM-MG, and MG-TSD. The emission peaks of K-TSD at 404.43 and 401.33 eV, attributed as protonated with greater electron binding and non-protonated respectively [63,64,65]. According to previous studies N1s peak of secondary -NH and -NH2+ observed at 398.08 eV and 400.33 eV in the GM-MG extrudate [66], N1s peak at 399.58 eV and at 401.28 eV in MG-TSD spectra correspond to secondary amine and -NH2+ respectively. Results of XPS confirmed the ion pairs with GM alkalizers that further confirmed through molecular model.

Molecular docking

The molecular docking has been used to describe potential intermolecular forces [54]. In present study following technique use to improve dissolution and degree through ion complexes in drug as shown in figure 11 shows MD conformation of GM with GM, alkalizers and lastly to Kollidon® VA64. The height of hydrogen bond between two GM molecules is 2.185 Å with binding energy is 15.87 kcal/mol. The distances between carboxylic group of GMH+ and protonated secondary amine of MGH+ were 1.54 and 1.94 Å, respectively, while distances between carboxylic acid groupof GMH- and protonated secondaryof KH+ were 1.51 and 2.14 Å with binding energies -23.56 and -17.67 kcal/mol, respectively. The distance of protonated secondary amine of MGH+ and Kollidon® VA64 was 1.47 and 3.22 Å respectively, while 2.599 and 2.923 Å distances between protonated secondary amine of KH+ and Kollidon® VA64 with bonding energies -3.58 and 25.94 kcal/mol respectively. Intermolecular H-bonds repeatedly form between GM molecules by their -COO groups and -OH groups, because of high electronegativity of the oxygen atoms. Mostly decreasing the bond length may stronger the bond [67,68], such forces responsible for the weak solubility of GM [69,70]. As according to present results weak binding energies with short bond length is responsible for strong hydrogen bonding in GM, while such binding energy is much less in case of GM-alkalizers complex due to interactive forces between drug and alkalizers molecules that disrupt the crystal characteristics of GM. On the other hand GMMG complex shows low binding energy in ionic form as compared to GM-K ionic complex but MG-VA extruadate K complex noted with high bond energy than of K extrudate [69] which explain the statement that MG-TSD shows high dissolution than K-TSD. Concussively combined complex of all such ingredients improve dissolution and solubility of GM by disrupting hydrogen bond interaction with Kollidon® VA64.

Solubility and dissolution

Both parameters were investigated for pure GM and SDs at different formulations observed in different buffers. (Figure BSD and TSD in buffer of pH 1.5 shows little difference than in BSD with buffer of pH 4.5, although MG-TSD was observed with high solubility than K-TSD. Similar trend was noted for pH range from 6.8 to and 8.0. Thus all formulations observed with improved dissolution as well as solubility for GM in presented range of pH i.e. 1.5-8.0 in vitro than API as shown in figure 12b). However, wettability of GM or drug improved by hydrogen bonding between Kollidon® VA64 and alkalizers. Such results indicate that the intermolecular forces in SD are important physical parameter for improving dissolution and solubility of GM [69-71].

 

CONCLUSIONS

The ternary solid dispersion technique is considered useful to improve dissolution and thus solubility of ionic form drug like Glimepiride Lysine (K) and MG in solid dispersion models prominently increased the rate of dissolution in different buffers of variable pH. Thus crystalline characteristics of GM would vanish to amorphous as noted in DSC and XPRD data. Ionic interpretation of GM with alkalizers was noted through FTIR, Raman, and XPS models. Amorphous appearance and ionic formation of GM were outstanding factors to improve dissolution in acidic strong media which leads to super-saturation of drug. This is another contributing factor to enhance dissolution of glimepiride. Our future focus will be to conduct study on GM bioavailability and its other pharmacological characteristics even at molecular level in vivo.

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Received : 10 Nov 2021
Accepted : 08 Dec 2021
Published : 10 Dec 2021
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