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Formulation and Optimization of Lyophilized Selexipag Nanocrystals to Improve the Saturation Solubility and Dissolution Rate

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Formulation and Optimization of Lyophilized Selexipag Nanocrystals to Improve the Saturation Solubility and Dissolution Rate Sys Rev Pharm 2020;11(11):596-605 A multifaceted review journal in the field of pharmacy Formulation and Optimization of Lyophilized Selexipag Nanocrystals to Improve the Saturation Solubility and Dissolution Rate Rusul M. Alwana*, Nawal A. Rajab, Areej W. Alhagiesac a* b Ministry of Health and Environment, Najaf health department, Najaf, Iraq. c Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq * Department of Pharmaceutics, College of Pharmacy, University of Kufa, Najaf, Iraq Corresponding author Email: [email protected] Phone number: 07831480928 Abstract Selexipag is first in class orally active, selective non- Keywords: Selexipag, Nanocrystal, nanosuspension, prostanoid prostacyclin receptor agonist with a long half- Selexipag nanocrystals. life. It has low oral bioavailability due to a poor dissolution rate, which is considered a rate-limiting step for drug absorption. Nanocrystals (NCs) formulation is an attractive approach for enhancing the poorly soluble drug's saturation solubility and dissolution rate. They offer the advantages of crystalline state, high drug loading capacity, and simple preparation method. This study aims to prepare and characterize Selexipag NCs, filled in hard gelatin capsule in attempt to improve its solubility and dissolution rate. The effect of stabilizer type and preparation methods on the NC particle size and polydispersity index were evaluated to select the most stable formula. The results revealed that the formula (F7) prepared by the solvent antisolvent precipitation with the ultrasonication method (which contain SLX: Soluplus® at a ratio of 1:2) has the smallest mean particle size (38.5 nm) and appropriate polydispersity index (0.12); hence it was selected as the optimal formula. Simultaneously, the data from powder X-ray diffraction shows no reduction in the crystallinity of drugs. SLX NCs exhibit increased saturation solubility by several folds than pure SLX. The hard gelatin capsule containing the lyophilized powder showed a faster dissolution profile (complete drug release in 15 min) relative to pure SLX (0.1% during the same time). 1. Introduction believed to play a particular role in PAH progression [1, Pulmonary arterial hypertension is an intractable life- 2]. threatening disease with a very poor prognosis despite SLX is an orally administered drug used for PAH many treatment options. PAH is characterized by treatment to delay disease progression and reduce vasospasm and vascular remodeling, resulting in right hospitalization risk. It is a selective IP receptor agonist ventricular dysfunction and eventually right heart failure with a long half-life. The activation of the IP receptor by 5an96d death. Decreased prostacyclin (IP)SypsrteomduacttiiconReivsiews in PShLaXrmleadcys to vasodilation and anti-proliferation of the Vol 11, Issue 11, Nov-Dec 2020 Formulation and Optimization of Lyophilized Selexipag Nanocrystals to Improve the Saturation Solubility and Dissolution Rate vascular smooth muscle cell. The advantages of such lyophilization of the selected formula to dry powder to be selectivity include: minimizing off-targeting effects, filled into a hard gelatin capsule and compared their especially to the gastrointestinal tract, and avoiding the 2di.sMsoaltuetrioianlspraonfdilemweitthoadpsure drug-loaded capsule. developmentⅠofⅡtacⅢhyphylaxis [3]. 2.1. Materials SLX is a crystalline powder with various pⅡolymorphic forms (form , , ). It is a lipophilic molecule (log P is 2.2) and practically insoluble in water (class , according Selexipag (SLX), hydroxypropyl methylcellulose (HPMC to BCS). SLX shows a pH-dependent solubility (insoluble E15), Poloxamer-407 (PXM-407) were bought from at pH 2 to 4 and freely soluble at pH 8). It has low oral Hangzhou Hyperchem limited (China). Soluplus® was bioavailability (49%) due to the poor dissolution profile purchased from BASF (Germany). Sodium hydroxide was of SLX [4–6]. 2pr.2o.vPidreedpabryatAilopnhaofcShLeXmNikSa (India). Hard gelatin capsule Nanocrystals (NC) are crystalline particles of the pure 2si.z2e.15. wAcaisdo-btaasienendeufrtormaliCzaaptsiounlinmee(tUhSoAd). drug in the nanometer range stabilized by polymer or surfactant. NCs platform is an effective strategy for enhancing the saturation solubility and dissolution rate of SLX (10 mg) was entirely dissolved in 3ml of 1N NaOH poorly soluble or insoluble compounds by reducing the (pH 12) under sonication for 5 min. Then this solvent particle size, leading to provide high surface area and phase was added dropwise by a syringe pump at a flow noticeable improvement in the oral absorption [7]. rate of (1ml/ min) into 27 ml of 0.1N HCl (pH 1.2) Drug NCs are typically formulated in liquid dispersion containing 20 mg of polymeric stabilizer (Soluplus®, PVA, media; hence they are called nanosuspension (NS). PXM-407, and HPMC E15) under continuous stirring for 1 Although NS has many unique properties, the physical 2hr.2a.2t .5P0r0ercpipmi,tastisohno-wulntrianstoanbileca(t1i)o[n1m1]e. thod (sedimentation/ creaming, crystalline state change, and aggregation) and chemical (hydrolysis) stability issue remains the main drawback of using it as a drug delivery SLX (10 mg) was dissolved in methanol (3 ml) under system. Thus, to overcome this problem, NS is usually sonication for 5 min. This organic solution of SLX was converted into solid-state, further processing into a solid added dropwise at a flow rate of (1ml/min) into 27 ml of dosage form (tablet and capsule). Lyophilization is an an aqueous solution containing 20 mg of polymeric efficient process for the solidification of NS. It involves stabilizer ( the same type of polymer used in the first removing water by sublimation process and then method ) with the aid of the syringe pump under stirring desorption of unfrozen liquid under high vacuum or low at 500 rpm and then followed by sonication with probe temperature. It is essential that after freeze-drying, dry sonicator at 90% amplitude for 2 min. The period of nanoparticles provide rapid re-dispersibility after ultrasound burst was set to 15 seconds with a pause for hydration and keep an initial particle size of the original 15 seconds between two ultrasound bursts. SLXNS was NS [8–10]. stirred for 1 hr to ensure complete evaporation of the This study aims to prepare and characterize SLXNS to organic solvent, as seen in table (1) [12]. Tenahbalenc1e. its solubility and dissolution rate. Then Formulation SLX (mg) Stabilizer used Drug: stabilizer ratio Preparation method F1Composition of SLXNS Formulas F2 F3 10 HPMC E15 1:2 acid-base neutralization F4 10 PVA 1:2 acid-base neutralization F5 10 Soluplus® 1:2 acid-base neutralization F6 10 PXM-407 1:2 acid-base neutralization F7 10 HPMC E15 1:2 Precipitation-ultrasonication F8 10 PVA 1:2 Precipitation-ultrasonication 10 Soluplus® 1:2 Precipitation-ultrasonication 2.3. Lyophilization of SL1X0NCs PXM-407 1:2 ℃ Precipitation-ultrasonication temperature 25 , measurement time 100 second, and The optimal SLXNS formula was converted into dried each sample were read three times without dilution. powder by lyophilization technique. Mannitol was used 2T.h4e.r2e.fSotraebaillitryeasdtusdreiepsresent the mean ±SD [14]. as a cryoprotectant at a concentration five times the total solid content in the selected formula. Mannitol was added ℃ into NS and vigorously shaking until mannitol was The SLXNS formulas with PS under 100 nm were stored completely dissolved. This sample was then ke℃pt in a at 4 for a week. The PS, PDI, and drug concentration freezer at -20 °C for 24 hrs. The frozen sample was then change at (0 and day 7) were recorded. Day 0 was the day freeze-dried using a labconnco lyophilizer at -52 and a of preparation [15]. The drug concentration was vacuum pressure of 0.2 mBar for 72 hrs to obtain the evaluated by taking an aliquot (1ml ) of the SLXNS and 2dr.4ieCdhpaorwacdteerr[i1z3at]i.on of SLXNS diluted with methanol up to 20 ml. Then these samples 2.4.1 Measurement of the particle size and were analyzed using a UV–visible spectrometer at polydispersity index 29.57..C8nhmar[a1c6te].rization of solid-state dry powder ( 2.5.1. Drug content in lyophilized powder The particle size (PS) and polydispersity index PDI) of all formulations were determined by dynamic light A specific amount of the freeze-dried powder equivalent scattering technique (DLS) using the ABT-9000 Nanolaser to 1 mg SLX was accurately weighed then dissolved in 25 Particle Size Analyzer under the following conditions; ml methanol under sonication for 5 min. The sample was 597 Systematic Reviews in Pharmacy Vol 11, Issue 11, Nov-Dec 2020 Formulation and Optimization of Lyophilized Selexipag Nanocrystals to Improve the Saturation Solubility and Dissolution Rate filtered and analyzed spectrophotometrically for drug (CI) value was had, the better the flow properties [22]. d d content at 297.8 nm. The study was done in triplicate, and 2CI.5=.6{T. dPo–wBde/rTX}-*r1a0y0d…if…fr.aEcqt.io(6n)(PXRD) the percent drug content was calculated according to equation (1) [17]. Drug content %= (observed drug content / Theoretical The crystallinity state of pure SLX and selected 2dr.5u.g2c. oRnetdeinstp)e*r1s0ib0i…lit..y.Eiqn.d(1e)x.) RDI) lyophilized formula were analyzed using a powder X-ray diffractometer (Shimadzu-6000, Japan). The sample was scanned over a range of 5° to 60° (2θ), the operating The redispersibility for lyophilized powder was 2vo.6lt.agFeill4in0gKvo, fanSdLaXculyrroepnhtiolifze3d0mpAow[2d3e].r into a hard determined by redispersing the known weight of the gelatin capsule freeze-dried powder in 2.7 ml distilled water with vigorous shaking to obtain the same concentration of drug in aqueous SLX NCs before lyophilization. The PS After knowing the formulation tapped density and the was measured as described in section 2.4.1. After that, the anticipated dose, the lyophilized powder equivalent to 1 RDI value was calculated according to equation (2). mg SLX was packed manually into the hard gelatin 0 RDI= (D /D ) *100%....... Eq. (2) capsule of a suitable size. 0 2.7. In vitro dissolution study The D represents the PS of redispersed NS, and D in vitro represents the PS of the pre-freeze-dried NS.
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