Molecular Weight Effect of Different Grades of HPC Polymer

molecular(a) Weight final result of Different Grades of HPC PolymerIntroductionBioavailability enhancementWet media mill around + spray dryingIssues ask intrusion on play per strivingance noneelty of the work aimMaterial and methods wet stirred media milling atomizer dryer movie techniquesResults and discussionstrong-arm stableness of the mill about precursor rifts medicine respite kineticsFormation of the NCMPs via spray drying of the precursor medicate gapsImpact of contrary polymers on the medicine decomposition from NCMPsPVP-K30HPMC-E3HPC-SSL, HPC-SL, HPC-LMolecular tilt consummation of antithetic grades of HPC polymer on dose radioactive decay performance and perceptual constancyIt is estimated that a life-size percentage of newly developed do doses compounds have limited bioavailibity receivable to their poor irrigate solubility and very slow looseness of the bowels regularize 1. According to the Biopharmaceutics Classification System (BCS), class II medicines atomic number 18 categorise as sick water oil-soluble and highly permeable in human body 2. To achieve the therapeutic efficacy of these medicines it is very immanent to enhance the bioavailability by increasing the solubility or disintegration commit. A number of approaches have been developed over the time to resolve this restitution. The lessening of drug particles size to sub-micron or nanometer has been one of the some habitual and strengthive approaches of wholly 3-6. By reducing the particles size order of magnitude, detail surface ara of the particles increased radic completelyy and enhances the dictate of absorption and dissolving 7, 8, according to the Noyes-Whitney equation 9. medicate nanoparticles yield technologies are classified into bottom-up or Top-d ingest or combining of both. The bottom up techniques accommodate precipitation employ supercritical fluid, liquid anti-solvent precipitation, and evaporative precipitation, where sm in all drug particles are produced from drug molecules dissolved in organic solvent 10, 11. In case of top-down approaches, the particles are reduced to the nanometer range 11. gritty pressure homogenization 5 and wet media milling 3 are included in top-down approaches. To prepare drug nanosuspension, wet stirred media milling (WSMM) has achieved the most popularity beca engage of its effectiveness, robustness, scalability, high drug loading, and low polymer side effects 5, 12, 13.Due to many advantages of drug solid venereal infection form, it is the most popular dosage form to the patients/clinicians. To encounter this high demand, drug nanosuspensions are usually converted into nanocomposite microparticles (NCMPs) exploitation dissimilar drying techniques and incorporated into standard solid dosage forms such as tablets and capsules 13, 14. Vacuum dryer 15, 16, spray-freeze dryer 17, 18, spray dryer 19, 20, and fluidized bed 17 are very prevalent and widely utilize drying tools i n the pharmaceutical industries. Among all the drying techniques, spray drying has already got attention due to its pushing intensive, continuous and ascendible drying process characteristics and ability to produce micro to nano-sized particles with a very peg down distribution within a very short time arrange 21.Albeit particle size reduction is an effective technique for bioavailability enhancement, stability issue has of all time been critical for the efficacy of the drug products. In the nanosuspension, drug particles assume losing their proper(postnominal) surface area by aggregation due to congenatorly high surface energy and unique(predicate) surface area and besides for enhanced Brownian motion 22. For the prevention of aggregation in the wet media and having discontinue stability, polymers and/or bedwetters are added to the suspension as stabilizers. These stabilizers endure stability by electrostatic or electrosteric mechanisms 22. Steric stability provided by the polymer is drug specific. Only some polymers can help to reduce the particle size of a specific drug down to nanometers. Therefore, selecting a proper stabilizer for a specific drug is a very complex process and cannot be reason out easily 23. Thus, having a break away insight about the polymer properties is very critical to figure out the right stabilizer for a particular drug. Molecular weight of the polymer is a very significant property of polymers, which determines the capability for steric stabilization along with solution properties 24, 25, regulates mechanical property of the films 26, and controls the drug release during vocal administration 27. Consequently, optimum MW and polymer concentration may help to get the better stabilization performance during and aft(prenominal) milling, and faster drug release from the composites. Choi et al. 16 investigated the impact of lower range MW (11,200-49,000 g/mol) of hydroxypropyl cellulose (HW) on itraconazole suspensi on production and their recovery from the drug composites. In that work, HPC was used solely with the same concentration, and dissolution performance hire was absent. Sepassi et al. 28 studied MW effect of two different polymers hydroxypropylmethyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) on the particle size reduction of milled nabumetone and halofantrine suspensions however, drying and dissolution rate were not studied. Li et al. 29 studied the MW and concentration effect of hydroxypropyl cellulose (HPC) on the dissolution performance of poorly soluble drug griseofulvin (GF) in front end/absence of sodium dodecyl sulfate (SDS) as surfactant. In that investigation, drug nanosuspension was surface and alter on to the surface of pharmatose using fluidized bed technique and likewise determined the optimum concentration and MW effect of HPC for complete release of the drug particles during dissolution.To authors best knowledge, no comprehensive and systematic study has bee n performed so farthermost to get the insight about the head to head comparison of different polymers performance and MW effect of the same polymer on the suspension stability after milling and during dissolution of NCMPs produced via spray drying. It is known from prior study that the unite use of polymers and surfactants provide a synergistic effect leading to better stability in the nanosuspension than individual stabilizers 30, 31. Due to the side effects of surfactant, it is always reckoned to use minimal amount in the verbal expression. If only the use of polymer can provide substantial stability in the nanosuspension and immediate release of the drugs in the dissolution from NCMPs, thusly it is more viable than using surfactant. Therefore, this study aims to develop an to a lower placestanding of the polymer MW and different polymer effect on the physical stability of Itraconazole nanosuspension and drug dissolution from the composites. Itraconazole (ITZ) suspensions wer e milled in a WSMM and the nanocomposite particles were produced using a co-current spray dryer. Three different polymers HPC, PVP, and HPMC were used at 4.5% (w/w) concentration to see the polymer effect and for MW effect, trinity grades (SSL, SL, and L) of HPC having different MW were used. Laser diffraction, SEM, UV- spectroscopy, XRPD, and DSC were used to analyze the drug suspension and composite particles. breakup test of the NCMPs were performed by a USP II paddle apparatus.MaterialsItraconazole (ITZ), is an antifungal drug with a water solubility 0.13 mg/L (at pH-7 and 25 C), is a meagrely water soluble drug belong to the BCS Class II was purchased from Jai Radhe gross revenue (Ahmedabad, India) and was used as-received condition. Three different polymers, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), and polyvinylpyrrolidone (PVP) were used as polymers. Three grades (SSL, SL, and L) of HPC with 40, nose candy, and cxl kDa molecular weight, menti onively, were donated by Nisso America Inc. (New York, NY, USA) and used for steric stabilization. Polymeric stabilizers Methocel E3 grade HPMC and PVP Kollidon 30 were donated by Dow chemical substance (Midland, MI, USA) and BASF Corporation (Florham Park, NJ, USA) respective(prenominal)ly. Sodium dodecyl sulfate (SDS) is an anionic surfactant used as a wetting agent during dissolution and provide electrostatic stabilization in the suspension, was purchased from Sigma Aldrich (Milwaukee, WI, USA). Zirmil Y grade wear-resistant yttrium-stabilized zirconia (YSZ) with a median size of 430 m (four hundred m nominal size) was used as the milling media and purchased from Saint Gobain ZirPro (Mountainside, NJ, USA).MethodsWet Stirred Media Milling (WSMM)The presuspension ( in advance milling) was prepared future(a) the same procedure used in Afolabi et al. 32. All the suspension formulations are tabulated below in Table 1. API (Itraconazole) concentration was kept constant at 10% (w/w) a nd polymer concentration was 4.5% (w/w) for all the formulation. All the concentrations are reported with respect to deionized water (200g). The formulation with 2.5% (w/w) HPC-SL and 0.2% (w/w) SDS was used as a baseline formulation, because from precedent study it was found to be the optimum for fastest and complete drug release from the composite powderizes.Prepared drug suspension was milled in a Netzsch wet media mill (Micorcer, Fine Particle Technology LLC, Exton, PA, USA) with 80 ml chamber 50 ml of the chamber was filled with 400 m (nominal size) Zirconia beads, which is the milling media and a screen with 200 m opening was used to hold the beads into the chamber and allowing only the handing over of the suspension. A rob mixer (Fisher scientific Laboratory Stirrer, Catalog No. 14-503, Pittsburgh, PA) was used to prepare the suspension prior to transfer into the holding store of the miller. The suspension was pumped through a peristaltic pump and was milled under the f ollowing conditions suspension flow rate 126 ml/min, rotor vivify 4000 rpm corresponding to a tip speed of 11.7 m/s. To documentation the suspension temperature below 35 C, milling chamber and holding armored combat vehicle both were equipped with a chiller (Advantage Engineering Greenwood, IN, USA). All the parameters were selected from the forward work done by Afolabi et al. 31. To determine the severance kinetics, particle sizes were thrifty at different time intervals up to 65 minutes and the suspension were refrigerated at 8 C for one day onward spray drying.Preparation of NCMPs via Spray DryingThe prepared nanosuspesions were dried within a day of milling using a spray dryer (4M8-Trix, Procept, Zelzate, Belgium) cart track in a co-current flow set up. All the operating conditions were interpreted from Azad et al. 19.The suspensions were atomized at 2 bar atomizing pressure using a bi-fluid bird of night having 0.6 mm tip diameter. In each run, 120 gm nanosuspensions were sprayed at 1.3-1.6 g/min spray rate using a peristaltic pump (Makeit-EZ, Creates, Zelzate, Belgium). Drying air was fed co-currently from the top of the column at 120 C temperature and 0.37-0.40 m3/min volumetric flow rate. To avoid sedimentation of the drug particles during spraying, the suspension was stirred using a magnetic stirrer throughout the run. A Cyclone separator was used at 54-70 mbar differential pressure to separate the NCMPs from the way out air stream and collecting them in a glass jar. The dried powders later on were used for powder pattern characterization e.g., XRD, DSC, Rodos, and dissolution testing.Particle Size AnalysisParticle size distributions of the suspensions were measurable at different time interval during milling and after 7-day storage in the refrigerator by laser diffraction (LD) technique using Coulter LS 13 320 (Beckman Coulter, Miami, FL). All the steps involved for measuring PSDs of the suspensions were followed from Li et al. 29. Durin g sample addition, color was maintained between 40-45% while obscuration was below 8%. Mie scattering possible action was used to compute the volume-based PSDs in the software. Refractive index value is 1.68 for ITZ and 1.33 for deionized water (spiritualist). Before measuring the PSDs, 2 ml suspension sample was composed from the outlet of the mill chamber and diluted with 5 ml of the respective stabilizer solution using a vortex mixer (Fisher Scientific Digital Vortex Mixer, Catalog no 0215370, Model No 945415, Pittsburgh, PA) at 1500 rpm for 1 min.The Particle size distributions (PSDs) of produced NCMPs via spray drying were measured by Rodos/Helos laser diffraction (LD) system (Sympatec, NJ, USA) based on Furnhofer theory with dry powder dispersion module. On the sample chute of the Rodos dispersing system, just about 1 g of the sample was located. To feed the samples, the sample chute was vibrated at 50% settings and 0.1 bar dispersion pressure was imposed to suck in the dr opping powder through the sample cell of the laser diffraction system.Determination of Drug Content in the Composite PowdersDrug content of the composite powders were measured by assay testing. ITZ solubility is - in dichloromethane (DCM). 100 mg of the NCMPs was dissolved in 20 ml DCM, sonicated for 30 mins to ensure all the ITZ is dissolved in the solvent and then they were allowed to sediment overnight. An aliquot of 100 l is interpreted from the supernatant and diluted to 10 ml with DCM. The absorbance of all the samples was measured at 260 nm wavelength via Ultraviolet (UV) spectrophotometer (Agilent, Santa Clara, CA, USA). Six replicates were prepared from each NCMP formulation to calculate mean drug content and percent relative standard deviation (RSD).Scanning Electron Microscopy (SEM)SEM imaging was performed to understand the word structure and particle size of the ITZ particles before and after milling. SEM images of as-received ITZ and baseline formulation was taken usi ng a LEO 1530 SVMP (Carl Zeiss, Inc., Peabody, MA, USA) SEM machine. Approximately, 0.1 ml milled suspension sample was placed on top of a silicon chip (Ted Pella Inc., Redding, CA, USA), and then on top of a carbon specimen holder. The sample was placed into a desiccator for overnight drying. The samples were then sputter coated with carbon before analyzing 33.X-ray Powder Diffraction (PXRD)The crystallinity of the as-received ITZ, physical mixed bag of ITZ-excipinets, and spray dried powders were examine using PXRD (PANalytical, Westborough, MA, USA), provided with Cu K radiation (= 1.5406 ). The samples were scanned at a rate 0.165 S-1 for 2 ranging from 5 to 40.Differential Scanning Calorimetry (DSC)DSC of the as-received ITZ, Physical mixture of ITZ-excipients, and spray dried powders was performed using a Mettler-Toledo polymer analyzer (PolyDSC, Columbus, OH, USA). The samples were heated at a rate of 10 C/min within a range of 25-220 C under nitrogen gas flow. With the hel p of the integrate software of the machine, melting temperature Tm and fusion enthalpy Hm were determined.Dissolution TestingDissolution of ITZ from the as-received drug, and spray dried composite powders were determined via a Distek 2100C dissolution tester (North Brunswick, NJ, USA) according to the USP II paddle method. The dissolution medium was 1000 ml SDS buffer with 3.0 gm/ml concentration at non-sink condition. The medium was maintained at 37 C temperature and 50 rpm paddle speed. The composites were weighed equivalent to a dose of 20 mg of ITZ. Composites were poured into the dissolution medium and manually 4 ml of samples were taken out at 1, 2, 5, 10, 20, 30, and 60 min. Aliquots of the samples were filtered using a 0.1 m PVDF membrane type spray filter to avoid any effect of undissolved drug during UV spectroscopy measurement. The absorbance of ITZ dissolved was measured via UV spectroscopy (Agilent, Santa Clara, CA, USA) at 260 nm wavelength. The blank was measured us ing SDS buffer at the beginning. The amount of drug dissolved was measured using a calibration curve generated from drug concentration vs. absorbance (R2=0.9995 with pApparent Shear Viscosity of mill ITZ SuspensionsThe evident shear viscosity of the nanosuspension was measured by following the procedure from Afolabi et al. 32, using R/S plus rheometer (Brookfield Engineering, Middleboro, MS, USA). To impart controlled shear rate on the samples from 0 to 1000 1/s in 60 s, a coxial cylinder (CC40) was used. To control the temperature the jacket temperature was kept constant at 250.5 C.Drug nanoparticles formation and physical stability of the milled suspensionsThe formulation of the milled drug (ITZ) suspensions are presented in Table 1. Drug (ITZ) nano suspension was outgrowth produced in presence of both steric and an anionic surfactant, SDS (Run 1). Due to the synergistic effect of HPC and SDS 31, Run 1 was used as a baseline to appreciate the impact of various stabilizers (HPC , HPMC E3, PVP k30, and SDS) in their breakage kinetics and physical stability of the resulting suspensions. This baseline formulation was found to be the optimum formulation from a previous work performed by Meng et al 29. The molecular weight effect of HPC was then studied in absence of SDS surfactant (Run 2-4) using three different grades of HPC SSL, SL, and L grades having molecular weight 40, 100, and 140 kDa, respectively.The apparent shear viscosity of all the formulations (Run 1-7) are represented in Figure 1. Formulations with 2.5% (w/w) HPC-SL/SDS, 4.5% (w/w) HPC-SL, and 4.5% (w/w) HPC-L (Run 1, 3, and 4) are display near Newtonian behavior, indicating the extent of aggregation is very low. Milled drug suspensions stabilized by SDS or polymer alone (except HPC-SL and HPC-L) are showing significant shear-thinning behavior, indicating significant amount of aggregates.References1.Kesisoglou, F., S. Panmai, and Y. Wu, Nanosizing-oral formulation development and biopharmaceuti cal evaluation. Advanced drug manner of speaking reviews, 2007. 59(7) p. 631-644.2.Amidon, G.L., et al., A theoretical basis for a biopharmaceutic drug motley the correlation of in vitro drug product dissolution and in vivo bioavailability. pharmaceutical research, 1995. 12(3) p. 413-420.3.Merisko-Liversidge, E. and G.G. Liversidge, Nanosizing for oral and parenteral drug delivery a perspective on formulating poorly-water soluble compounds using wet media milling technology. Advanced drug delivery reviews, 2011. 63(6) p. 427-440.4.Panagiotou, T. and R.J. Fisher, Form nanoparticles via controlled crystallization. Chemical Engineering Progress, 2008. 104(10) p. 33-39.5.Keck, C.M. and R.H. Mller, Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. European daybook of Pharmaceutics and Biopharmaceutics, 2006. 62(1) p. 3-16.6.Mller, R., C. Jacobs, and O. Kayser, Nanosuspensions as particulate drug formulations in therapy rationale for development and w hat we can expect for the future. Advanced drug delivery reviews, 2001. 47(1) p. 3-19.7.Singh, S.K., et al., Investigation of preparation parameters of nanosuspension by top-down media milling to improve the dissolution of poorly soluble glyburide. European daybook of Pharmaceutics and Biopharmaceutics, 2011. 78(3) p. 441-446.8.Tanaka, Y., et al., Nanoparticulation of probucol, a poorly water-soluble drug, using a fresh wet-milling process to improve in vitro dissolution and in vivo oral absorption. Drug development and industrial pharmacy, 2012. 38(8) p. 1015-1023.9.Noyes, A.A. and W.R. Whitney, The rate of solution of solid substances in their own solutions. Journal of the American Chemical Society, 1897. 19(12) p. 930-934.10.Sun, B. and Y. Yeo, Nanocrystals for the parenteral delivery of poorly water-soluble drugs. Current Opinion in Solid State and Materials Science, 2012. 16(6) p. 295-301.11.Chan, H.-K. and P.C.L. Kwok, Production methods for nanodrug particles using the bot tom-up approach. Advanced drug delivery reviews, 2011. 63(6) p. 406-416.12.Bhakay, A., et al., Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs. Drug development and industrial pharmacy, 2011. 37(8) p. 963-976.13. caravan Eerdenbrugh, B., G. Van den Mooter, and P. Augustijns, Top-down production of drug nanocrystals nanosuspension stabilization, miniaturization and transformation into solid products. supranational journal of pharmaceutics, 2008. 364(1) p. 64-75.14.Basa, S., et al., Production and in vitro characterization of solid dosage form incorporating drug nanoparticles. Drug development and industrial pharmacy, 2008. 34(11) p. 1209-1218.15.Kim, S. and J. Lee, Effective polymeric dispersants for vacuum, convection and freeze drying of drug nanosuspensions. International journal of pharmaceutics, 2010. 397(1) p. 218-224.16.Choi, J.-Y., C.H. Park, and J. Lee, Effect of polymer molecular weight on nanocomminutio n of poorly soluble drug. Drug delivery, 2008. 15(5) p. 347-353.17.Wang, Y., et al., A comparison between spray drying and spray freeze drying for dry powder inhaler formulation of drug- make full lipid-polymer hybrid nanoparticles. International journal of pharmaceutics, 2012. 424(1) p. 98-106.18.Cheow, W.S., et al., Spray-freeze-drying production of thermally sensitive polymeric nanoparticle aggregates for inhaled drug delivery effect of freeze-drying adjuvants. International journal of pharmaceutics, 2011. 404(1) p. 289-300.19.Azad, M., et al., Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving, high drug-loaded, surfactant-free nanocomposites. Drug development and industrial pharmacy, 2015. 41(10) p. 1617-1631.20.Lee, J., Drug nanoand microparticles touch on into solid dosage forms physical properties. Journal of pharmaceutical sciences, 2003. 92(10) p. 2057-2068.21.Kemp, I.C., Fundamentals of energy analysis of dryers. Modern Drying Techno logy, 2011. 4 p. 1-46.22.Kim, C.-j., Advanced pharmaceutics Physicochemical principles. 2004 CRC Press.23.Lee, J., et al., Amphiphilic amino group acid copolymers as stabilizers for the preparation of nanocrystal dispersion. European journal of pharmaceutical sciences, 2005. 24(5) p. 441-449.24.Adamson, A. and A. Gast, Physical chemical of surfaces. 1997, New York Wiley.25.Ploehn, H.J. and W.B. Russel, Interactions between colloidal particles and soluble polymers. Advances in Chemical Engineering, 1990. 15 p. 137-228.26.Rowe, R., The effect of the molecular weight of ethyl cellulose on the drug release properties of mixed films of ethyl cellulose and hydroxypropylmethylcellulose. International journal of pharmaceutics, 1986. 29(1) p. 37-41.27.Mittal, G., et al., Estradiol loaded PLGA nanoparticles for oral administration effect of polymer molecular weight and copolymer composition on release behavior in vitro and in vivo. Journal of Controlled Release, 2007. 119(1) p. 77-85.28.Sepas si, S., et al., Effect of polymer molecular weight on the production of drug nanoparticles. Journal of pharmaceutical sciences, 2007. 96(10) p. 2655-2666.29.Li, M., N. Lopez, and E. Bilgili, A study of the impact of polymer-surfactant in drug nanoparticle coated pharmatose composites on dissolution performance. Advanced Powder Technology, 2016.30.Ryde, N.P. and S.B. Ruddy, Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate. 2002, Google Patents.31.Bilgili, E. and A. Afolabi, A unite microhydrodynamics-polymer adsorption analysis for elucidation of the roles of stabilizers in wet stirred media milling. International journal of pharmaceutics, 2012. 439(1) p. 193-206.32.Afolabi, A., O. Akinlabi, and E. Bilgili, Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling a microhydrodynamic view. European Journal of Pharmaceutical Science s, 2014. 51 p. 75-86.33.Li, M., et al., An intensified vibratory milling process for enhancing the breakage kinetics during the preparation of drug nanosuspensions. AAPS PharmSciTech, 2016. 17(2) p. 389-399.