INTRODUCTION:

Considerable modern active pharmaceutical ingredients belong to the BCS class II category and exhibit low solubility and low dissolution rates. Low solubility turns in an important chemical entity not arriving at a stage of finished pharmaceuticals by reason of not achieving their full potential and therapeutic range. These API needs enhancement in low solubility, dissolution rate and bioavailability which is featured to drug’s success. The most common long-term complication in patients suffering from diabetes mellitus is diabetic neuropathy.¹

EP is a relatively new widely prescribed endocrine and metabolic product, the subcategory is an antidiabetic drug which is a poorly water-soluble known to demonstrate solubility related dissolution constraint.^2-4Its mechanism of action is largely based on the inhibition of aldose reductase.^5-6 Aldose reductase enzyme of the polyol pathway converts glucose to sorbitol in presence of NADH. Increased aldose reductase expression has been associated with complications of diabetes, as it can create tissues dependent on insulin for glucose uptake. EP reduces oxidative stress in type II diabetes by decreasing lipid hydroperoxide levels in erythrocyte when administered at 150mg/day. Cyclodextrin complexation is a productive approach for enhancing the solubility, dissolution rate and bioavailability of BCS Class II Drugs. Cyclodextrins are a family of three well known, industrially produced, major cyclic oligosaccharides and several minor, rare ones. Cyclodextrins may be classified into major three types such as natural CDs, chemically modified CDs, branched CDs.⁷ The natural/parent cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, which consist of six, seven, and eight glucopyranose units, respectively.⁸ Low polarity central cavity of CDs which are torus-shaped molecules with a hydrophilic outer surface and a lipophilic central cavity, this central cavity is able to encapsulate, either partially or entirely, a variety of guest molecules of suitable size and shape resulting in a stable association, an entity known as inclusion complex. The inclusion complex involves the spatial entrapment of a single guest molecule in the cavity of host molecule without any covalent bonds being formed.^9-10 As a consequence of inclusion complexation, many physicochemical properties such as solubility, dissolution rate, stability, and bioavailability can be favorably affected.^11-14 For the number of reasons like cavity dimensions, availability, approval status, and price the parent CDs are the most widely preferred in pharmaceuticals. However, its low aqueous solubility (and low solubility of the most formed complexes) toxicology, the amount of cyclodextrins makes it a serious barrier in its wider utilization.^15-16Therefore, it is important to develop a plan to boost and expand the functionalities of CDs that could be resulted in a reduction in the amount of CD necessary in a particular drug formulation and overcome the low solubility by the drug CD binary complex. Hence the use of water-soluble polymer, for the preparation of drug/CD/polymer multi-component system, or the formation of CD ternary inclusion complex of drugs have been opted by researchers.^17-21 Moreover, the addition of a suitable third component can often significantly improve both the solubilizing and complexing potential of cyclodextrins with several drugs.²² Enhanced complexation can be achieved by formation of the ternary complex between the drug molecule, cyclodextrin, and a third component. Among all solubility enhancement techniques, the generation of an inclusion complex with CDs and a hydrophilic carrier is a promising option for increasing the aqueous solubility, dissolution rate, and bioavailability of poorly water-soluble drugs.^23-27

EP is in the Biopharmaceutics Classification System as a class II compound with high permeability but low aqueous solubility (47.9µg/mL)²⁸ with dissolution rate dependent absorption. For this reason, the aim of this study was to evaluate the influence of the hydrophilic polymer on the properties of a poorly soluble model drug, EP as well as to evaluate the effect of a drug–CD–polymer on the solubility of EP.

MATERIALS AND METHODS:

Epalrestat was a generous gift from Zydus Cadila Ahmadabad (India). β-CD, PVP K 30 and HPMC E4 were purchased from unique chemicals. All reagents and solvents used in the current investigation were of analytical grade.

Analysis of Epalrestat using a UV-visible spectrophotometer:

First, 100 µg/ml stock solution of EP was prepared in methanol and further dilutions were made in distilled water ranging from 03-18 µg/ml. The calibration curve was obtained by recording the absorbance on a UV spectrophotometer (Shimadzu UV spectrophotometer 1800) at 390nm by a method previously developed and validated.²⁹

Phase solubility Studies:

The solubility behavior of EP was analyzed in distilled water at room temperature (25±2°C) according to the method described by (Higuchi and Connors 1965)³⁰. An excess amount of EP (50mg) was added to 20 ml of aqueous solutions containing various concentrations of β-CD (1mM–10mM) with or without the addition of hydrophilic polymers (0.25%w/v) polyvinylpyrrolidone (PVP K30), and (0.25%w/v) hydroxyl propyl methyl cellulose (HPMC E4). The suspensions were mechanically shaken subsequently on a rotary shaker for 72 hr at 125 rpm until equilibrium was attained. The samples were filtered through Whatman filter paper, diluted if necessary and analyzed spectrophotometrically (Shimadzu UV spectrophotometer 1800) at 390 nm. The association constant (Ks) of complexes and complexation efficiency (CE) of β-CD were calculated according to the equations (1) and (2) respectively.³¹

Ks = Slope /S₀ (1-Slope) (1)

S₀is the solubility of EP in absence of β-CD and the slope is obtained from the phase solubility diagram obtained by plotting moles of the drug on y-axis and moles of β-CD on the x-axis. It gives an idea about the linear dependence of drug concentration to β-CD concentration, with slope ratio below one usually assumes 1:1 ratio of the complex and refers to A_L (linear) type of the phase solubility curve.

CE = S0.K _1:1 = Slope / (1-Slope) (2)

Preparation of solid complexes:

Preparation of binary complex by kneading:

The equimolar physical mixture of (1:1) was prepared by homogeneously blending exactly weighed amounts of drug and β-CD until the homogenous mixture is obtained and 1.5 folds of water to the total weight of the physical mixture was added slowly during continuous kneading. The mixture was kneaded for about 1 hour to get the paste. Then paste was dried at room temperature for 24 hours and then the dried powder sieved to obtain particles of uniform size.³²

Preparation of ternary complexes by kneading:

An equimolar physical mixture of (1:1) was prepared by homogeneously blending exactly weighed amount of drug and β-CD until the homogenous mixture is obtained and sufficient volume of 0.25%w/v and 0.25%w/v aqueous solution of polymers PVP K30 and HPMC E4 were added slowly during continuous kneading to get ternary complexes. The mixtures were kneaded for about 1 hour to get the paste. Then this paste was dried at room temperature for 24 hours and then the dried powder sieved to obtain particles of uniform size.³³

Characterization of Solid complexes:

Drug content and kneaded process yield:

10 mg of kneaded binary and ternary solid inclusion complexes were weighed accurately and extracted using 100 mL of phosphate buffer pH 6.8 by shaking for 12 hours on the rotary shaker. Filter sample through Whatman filter paper and after sufficient dilutions if required, samples were analyzed spectrophotometrically at 390nm (Shimadzu UV spectrophotometer 1800). Drug content was calculated from the standard curve of Epalrestat in phosphate buffer pH 6.8. Kneaded yield was determined by the co-relating weight of added solute with that of recovered one.

Fourier transform infrared spectroscopy (FTIR) Analysis:

FTIR spectroscopy was carried on a Fourier Transform Infrared Spectrometer (Alpha T Bruker) using the KBr disc method. Spectra (16 scans at 4 cm−1 resolution) were collected in the 4000–400 cm−1 range.

Differential scanning calorimetry (DSC) Analysis:

DSC curves of EP, β-CD and ternary complexes were recorded on a Mettler Toledo, Staresw 920. Thermal behavior was studied by the heating sample (2-4mg) in crimped aluminum pans at a scanning rate of 10⁰C/min in an atmosphere of nitrogen using the range of 100-240⁰C. Indium as a standard was used periodically to perform the temperature calibrations.

Powder X-ray diffractometry (PXRD) Analysis:

To access the changes in the crystallinity of the ternary complexes generated, the PXRD study was performed with X-ray diffractometer (Miniflex 600 X-Ray DiffractometerRigaku Corporation Japan). For this, the samples of pure drug, β-CD, and prepared ternary complex were irradiated with monochromatizedCuKα radiation, analyzed between from 5^° to 60^° and the diffractograms were recorded in the 2θ angle.

Scanning electron microscopy (SEM) Analysis:

The surface morphological aspects of EP, binary and ternary complexes were investigated using a scanning electron microscope (VEG A3 TESCAN) operated at an acceleration voltage of 20 kV and obtained microphotographs were examined at X500 and X2000 magnifications.

Saturation solubility studies:

Saturation solubility studies of EP, binary and ternary complexes were conducted. An excess amount of EP and complexes were added to 20 ml of distilled water in vials sealed with stoppers and shaken in rotary flask shaker at room temperature (25±0.5°C) for 24h. A portion of the solution was withdrawn, filtered through Whatman filter paper 41 and analyzed spectrophotometrically (Shimadzu UV spectrophotometer 1800) at 390 nm.

Dissolution studies:

Drug release studies were performed for EP and its kneaded binary and ternary complexes using USP Type-II (EDT 08LX Electrolab) dissolution test apparatus. Sample equal to 100 mg of EP was used in each test. 900 ml of phosphate buffer pH 6.8 at 37±0.5⁰C with 100 RPM were used to perform the dissolution test. Aliquots of the (5 ml) were periodically withdrawn filtered, appropriately diluted if required and analyzed, spectrophotometrically (Shimadzu UV spectrophotometer 1800) at 390 nm. 5 ml of fresh medium was transferred to maintain sink conditions.

Stability Study:

Binary and ternary complexes (kneaded solid systems) of EP studied for stability with the help of (Remi SC-19 Plus) by storing 1gm of each complex in amber colored screw-capped glass bottles at accelerated and controlled temperature 40⁰C and relative humidity (75%) for 3 months. At the end of three months, the complexes were evaluated for physical appearance, drug content and in-vitro dissolution.³³

RESULTS AND DISCUSSION:

Phase solubility studies:

The complexing behavior of EP with β-CD in water was studied by the phase solubility analysis according to guidelines given by Higuchi and Connors 1965. Fig.1 shows the phase solubility diagrams of EP with β-CD and that of PVP K30, HPMC E4. A typical B_S-type solubility diagram as stated by Higuchi and Connors classification system was shown by the EP and β-CD, binary complex. B_S-type phase solubility diagram indicates the development of inclusion complexes with limited solubility. The solubility of EP in distilled water was determined and found to be only (0.0467±0.002 mg/ml) but significant solubility increase was exhibited by the addition of β-CD. The increment of EP solubility seems to be associated with the inclusion capability of the CD molecules in water. The solubility of the binary complex was higher than a pure drug. The phase solubility profile of EP in aqueous β-CD solution in presence of 0.25% PVP K30 and 0.25% HPMC E4 exhibited A_L type of solubility curve with a linear increase in solubility of EP with increasing the concentration of β-CD. And slopes curves of phase solubility diagram were lesser than 1 representing the formation of a 1:1 stoichiometry water-soluble complex.

The values of Ks and CE of ternary complexes increased with the incorporation of the water-soluble carrier to the binary complex showing more fruitfulness of ternary systems over binary. The values of Ks were found to be 505.18 and 793.05 and 964.74 for binary complex and ternary complexes with PVP K30 and HPMC E4 respectively. Solubilizing effect of β-CD was increased in the presence of both PVP K30 and HPMC E4. Complexation efficiency of the binary complex was found to be 0.24 and for ternary complexes, it was 0.32 and 0.38 PVP K30, and HPMC E4 respectively which is greater in accordance with a binary complex.

Fig. 1 Phase solubility diagrams of EP: β-CD (Binary complex) and EP: β-CD: Water-soluble carriers (Ternary complexes) in water.

Drug content and yield of Kneading Process³⁴

The drug content of solid complexes was determined using a previously reported method.³⁵The practical drug content of binary and ternary solid complexes with0.25% w/v PVP K30, and 0.25% w/v HPMC E4 was found to be20.72±0.12, 20.12±0.16 and 20.18±0.23 respectively which corresponded to the ratio of the drug with the beta-cyclodextrin and hydrophilic polymer. The yield with the kneading process was found greater than 90%. The greater yield of the kneading process makes it a suitable method for preparation of binary and ternary complexation.³⁶ The theoretical drug content, practical drug content, and yield of the kneading process is summarized in table No.1

Table No 1: Drug content and yield of kneading process for the binary and ternary complex

Solid complexes (1:1molar stoichiometric ratio)	Theoretical drug content (%)	Practical drug content (%)	Yield of Kneading Process (%)
Binary complex	21.95	20.72 ± 0.12 9	94.39 ± 0.30
Ternary with PVP K 30	21.84	20.12 ± 0.16	92.12 ± 0.13
Ternary with HPMC E4	21.84	20.18 ± 0.23	92.39 ± 0.23

* Represents mean ± S.D. (n = 3)

Fourier-transform infrared spectroscopy (FT-IR):

To assess the interaction between β-CD, host molecule and guest molecules in the solid state, FT-IR spectroscopy has also been used. Fig.2 shows the FTIR spectra of pure drug, binary and ternary complexes. Principle absorption peaks were found near 1742, 1673, and 1555 cm−1 from carboxyl, amide, and thiocarbonyl stretching vibrations, respectively for pure drug EP. No significant changes of the characteristic peak of EP were observed in complexes indicating that no important interactions should be involved in the kneaded solid systems. All these principle characteristic peaks were retained and did not shift both in binary and ternary complexes. The binary, as well as ternary spectra, did not show new peaks indicating that no chemical bonds were created in the formed complexes. ³⁷This served to approve the existence of strong and firm interactions between EP, β-CD and water-soluble polymer, leading to generation inclusion complex and also may be expressive of uniform EP dispersion as a consequence of the interaction with β-CD and polymer.

Fig. 2. FTIR spectra of A) EP B) Pure β-CD C) Binary complex D) EP:β-CD: PVP(Ternary complex) E) EP:β-CD:HPMC E4 (Ternary complex)

DSC measurements:

DSC analyses were performed to evaluate the thermal behavior of EP, β-CD and ternary complexes, respectively Fig. 3 and interaction between EP and β-CD in complex formation. When guest molecule incorporated into a cyclodextrin central cavity, their melting point shifts to the different temperature or it may disappear. One sharp endothermic peak was observed near around 215⁰C contributed to the melting point of crystalline EP in the thermograms of pure drug. The DSC profiles of β-CD demonstrate liberation of crystal water as an endothermal effect appeared at about 140⁰C. In the ternary complex, the endothermic peak obtained from EP shifted its intensity was reduced this small change corresponding to the peak of a pure drug is indicative of a low interaction between the components in the ternary complex. It is concluded from DSC curves that EP and β-CD were molecularly dispersed in the amorphous form in the kneaded ternary complex.

Fig.3.DSC thermograms of A) EP B) Binary complex C) EP:β-CD: HPMC E4 (Ternary complex)

PXRD measurements:

PXRD patterns of EP, binary and ternary complexes are represented in Fig.4. The X-ray diffraction pattern of EP presented several high-intensity reflections suggestive of its crystalline character. Comparing the X-ray diffraction pattern of the pure drug with those of EP-β-CD, binary and the ternary system it is concluded that there were no marked differences between X-ray diffraction pattern of binary and ternary kneaded systems and all of them were a superposition of the pure component. The pattern of the ternary complexes could be interpreted as a superposition of EP and β-CD representing absences of crystalline traces of EP indicating entrapment of EP in β-CD. The PXRD showed a halo pattern and no diﬀraction peak occurred when EP was kneaded with β-CD at a 1:1 molar ratio. Crystalline EP turned amorphous by kneading with β-CD. It was revealed that the crystalline structure of EP was distorted indicating clear loss of EP crystallinity and EP molecules were converted into an amorphous state.

SEM analysis:

The surface morphological features of EP, binary and ternary complexes are shown in Fig. 5. Separate entities of crystals of the irregular shape of pure EP appeared (Fig. 5A). Binary complex particles exhibited an altered shape and agglomerate type morphology (Fig. 5B). Change in morphology of ternary complexes was observeddue to the crystalline nature of β-CD and water-soluble carrier (Fig. 5C) showing agglomerated images due to the kneading process applied for the generation of ternary complexes. The alerted morphology of particles of kneaded complexes indicates the existence of a single phase within the complex (crystals of the drug are sometimes partially or fully inserted in the carrier) attaining maximum complexation. ³⁸

Fig.5.SEM images of A) Pure EP B) Binary complex C) EP:β-CD: HPMC E4(Ternary complex)

Saturation solubility studies:

Solubility enhancement in both binary and ternary complexes as compared to pure drug EP was observed in the saturation solubility studies. The solubility of 47±0.04 µg/mL in distilled water was exhibited by pure drug EP. The binary and ternary complexes with PVP K30 and HPMC E4 have shown solubility of 98.7±0.30 and 170.20± 0.32µg/ml, and 179.10±0.30µg/ml respectively with 210% increment in the solubility of binary complex and 362.12% and 381.59% with PVPK30 and HPMC E4 resp. The increment in the solubility of the ternary complex was almost double than binary complex. Formation of stable inclusion complex of EP and β-CD, altered surface morphological features of the inclusion complexes due to kneading and inclusion into the hydrophobic β-CD cavity resulted in the enhancement in solubility of the complex. Significant role as an auxiliary ternary component by the water-soluble carrier in ternary complexes resulted in improved performance than binary complex.³⁸

Fig.6. Effect of kneading with β-CD and water-soluble carrier on EP solubility

In vitro dissolution studies:

EP and its corresponding binary and ternary complexes were evaluated for dissolution properties and compared to the pure EP. The in-vitro dissolution results were assessed on the basis of cumulative percentage drug release, dissolution efficiency and correlation coefficient (r).

The dissolution curves of EP and ternary complexes are shown in Fig.7. An enhancement in the dissolution profile was observed for solid complexes as compared to pure EP. The binary complex has shown almost 60% drug release in 60 min. And ternary complex demonstrated grater dissolution profile as compared to binary complex with 79% drug release within 60min in dissolution media. Phase solubility parameters such as Ks and CE were greatly promoted due to a positive effect of the addition of water-soluble carried and resulted in the greater fruitfulness of ternary complexes for higher release rate. Hence, we can arrive at a judgment that ternary complexes of EP with β-CD and the water-soluble carrier could be a reliable approach for dissolution enhancement.^39-45

Fig.7. The dissolution profile of pure drug, binary and ternary kneaded complexes

Stability Study:

There was no significant change in the physical appearance, drug content and percent drug dissolution in the EP complexes. Stability results clearly indicate that the complexes were sufficiently stable under accelerated and controlled conditions.

CONCLUSION:

The present investigation governs the utility of the β-CD and water-soluble carriers PVP K 30, HPMC E4 to enhance the solubility and dissolution rate of the poorly aqueous soluble drug Epalrestat. Dissolution study indicates that ternary kneaded product is most useful for enhancement of solubility of Epalrestat as compare to the drug alone. Formation of inclusion complexes greatly enhances the solubility of EP, which can thus increase its bioavailability and improving the therapeutic efficiency of the drug.

ACKNOWLEDGMENT:

Authors are thankful to Zydus Cadila Ahmadabad (India) for providing Epalrestat drug as a gift sample.

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Received on 12.02.2019 Modified on 18.03.2019

Research J. Pharm. and Tech 2019; 12(8): 3602-3608.

DOI: 10.5958/0974-360X.2019.00614.0