Purpose: Ticagrelor (TGR) is an orally active antiplatelet agent, indicated to reduce the rate of thrombotic cardiovascular events. It belongs to BCS Class-IV and having low LogP value 2. Gelucire 48/16® was evaluated to improve solubility and dissolution of TGR. It is a PEG 32 mono and diesters of stearic and palmitic acid, with an HLB of 16 and CMC of 153±31 mg/L, which helps to increase solubility of hydrophobic and lipophobic molecules. Being solid at ambient temperature with melting point of 48°C, makes Gelucire 48/16 a robust and suitable solid solubilizer for melt processes and tableting.
The objective of the present study was to prepare solid dispersions of TGR with Gelucire 48/16® by hot melt granulation technique to improve solubility of TGR followed by conversion of melt dispersion into granules by adsorbing on an inert carrier and compression into tablets.
Methods: In the present study, solid dispersions were prepared by hot melt technique to improve solubility of TGR. Gelucire 48/16 was melted at 70oC and TGR was dissolved in the molten mass. The binary melts of TGR and Gelucire 48/16 in the ratios of 1:0.5, 1:1, 1:1.5 and 1:2 were prepared and adsorbed on silicified microcrystalline cellulose. These ternary mixtures were sifted through ASTM #25 upon cooling to obtain granules and blended with extragranular ingredients followed by compression using suitable tablet tooling. The dissolution of tablets with all the ratios were carried out, where the ratio of 1:1.5 was found to be good in terms of dissolution and processing. The solid dispersion of selected ratio was evaluated for Differential Scanning Calorimetry, X-Ray Diffraction Study, Fourier Transform Infrared Spectroscopy, In-Vitro Dissolution of Tablets.
Results: Differential Scanning Calorimetry (DSC): Samples (5-10 mg) were sealed in aluminium pans for analysis. The DSC thermograms were recorded from 30oC to 300oC at a heating rate of 10oC/min. A nitrogen flow rate of 20 ml/min was used for each DSC run.
DSC thermograms indicates sharp endotherms of TGR and Gelucire 48/16 at 140.82°C and 50.02°C respectively. TGR is solubilized in the melt of Gelucire 48/16 which could explain the disappearance of TGR endotherm. Endotherm of TGR was not evident in the solid dispersions indicating a change in the physical state, attributing to its enhanced solubility.
X-Ray Diffraction (XRD) Study: Powder X-ray diffraction patterns of samples were recorded to assess the solid state of TGR, using a Phillips X-ray diffractometer with a copper target, voltage 40 kV, current 20 mA, at a scanning speed of 2o per min.
XRD pattern of TGR indicates its crystalline nature. Gelucire-48/16 shows a semi-crystalline nature. Physical mix shows the merging of peaks of drug with the peaks of Gelucire 48/16. Solid dispersion indicates change in the crystalline form of TGR in the matrix of Gelucire 48/16. Presence of adsorbent may prevent the reversion of the amorphous drug to crystalline state on storage of the solid dispersion.
Fourier Transform Infrared Spectroscopy (FTIR): The KBr disks of samples were prepared using electrically operated KBr Press. A PerkinElmer Fourier transform spectrophotometer was used to record IR spectra of the prepared discs, to confirm for any interaction of TGR with excipients of dispersion granules.
FTIR spectra shows- TGR has several characteristic peaks at 670, 1330, 1385, 1521, 1588 cm-1 . These peaks are of diagnostic value to elucidate drug-excipient interactions. These peaks are also visible in the spectra of physical mix, solid dispersion and dispersion granules. FTIR spectrum of dispersions did not reveal any significant drug excipient interaction.
Tablet Preparation: The granules were blended with extragranular ingredients i.e. silicified microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate and talc. The tablet blend was compressed into tablets using 11 mm round shaped convex punches on Eliza Press tablet compression machine. The tablets were evaluated for IPQC tests i.e. Hardness, thickness, disintegration time and friability.
In-Vitro Dissolution of Tablets: The tablets were evaluated for in vitro dissolution in 900 mL of 0.2% w/v of Polysorbate 80 in water using USP Type-II apparatus, at 75 rpm and 37.5±0.2C°. Dissolution of branded tablets was also performed. Analysis of the samples was performed on a UV spectrophotometer at λmax 220 nm after suitable dilutions.
Dissolution profile of in house tablets containing 1:1.5 ratio of TGR: Gelucire 48/16 showed remarkably improved dissolution compared to market reference.
Conclusion: Gelucire 48/16 was employed effectively to enhance the solubility and dissolution of a poorly water-soluble BCS Class-IV drug i.e. TGR. DSC and XRD studies indicated the change in physical state of TGR in Gelucire 48/16 matrix, which could be attributed to its enhanced solubility and dissolution rate. It can be concluded that Gelucire 48/16 is an effective solubilizing excipient for solubility and dissolution enhancement which could also lead to bioavailability improvement of poorly soluble molecules.
Ketkee Deshmukh– Technical Manager, Gattefosse India Pvt. Ltd., Mumbai, Maharashtra
Sharda Gurram– Lab Officer, Gattefosse India Pvt. Ltd., Mumbai, Maharashtra
Nabil Farah– Global Technical Director, Gattefosse SAS, Rhone-Alpes
Sunil Bambarkar– Managing Director, Gattefosse India Pvt. Ltd., Mumbai, Maharashtra