Molecular Weight Effect of Different Grades of HPC Polymer
Disclaimer: This work has been submitted by a student. This is not an example of the work written by our professional academic writers. You can view samples of our professional work here.
Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of UK Essays.
Published: Thu, 31 Aug 2017
- Bioavailability enhancement
- Wet media milling + spray drying
- Issues have impact on dissolution performance
- Novelty of the work
- Material and methods
- wet stirred media milling
- Spray dryer
- Characterization techniques
- Results and discussion
- Physical stability of the milled precursor suspensions
- Drug breakage kinetics
- Formation of the NCMPs via spray drying of the precursor drug suspensions
- Impact of different polymers on the drug dissolution from NCMPs
- HPC-SSL, HPC-SL, HPC-L
- Molecular weight effect of different grades of HPC polymer on drug dissolution performance and stability
It is estimated that a large percentage of newly developed drug compounds have limited bioavailibity due to their poor water solubility and very slow dissolution rate . According to the Biopharmaceutics Classification System (BCS), class II drugs are categorized as poorly water soluble and highly permeable in human body . To achieve the therapeutic efficacy of these drugs it is very essential to enhance the bioavailability by increasing the solubility or dissolution rate. A number of approaches have been developed over the time to resolve this issue. The reduction of drug particles size to sub-micron or nanometer has been one of the most popular and effective approaches of all [3-6]. By reducing the particles size order of magnitude, specific surface area of the particles increased radically and enhances the rate of absorption and dissolution [7, 8], according to the Noyes-Whitney equation .
Drug nanoparticles production technologies are classified into “Bottom-up” or “Top-down” or combination of both. The bottom up techniques include precipitation using supercritical fluid, liquid anti-solvent precipitation, and evaporative precipitation, where small 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 . High pressure homogenization  and wet media milling  are included in top-down approaches. To prepare drug nanosuspension, wet stirred media milling (WSMM) has achieved the most popularity because of its effectiveness, robustness, scalability, high drug loading, and low polymer side effects [5, 12, 13].
Due to many advantages of drug solid dosage 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) using different 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  are very prevalent and widely used drying tools in the pharmaceutical industries. Among all the drying techniques, spray drying has already got attention due to its energy intensive, continuous and scalable drying process characteristics and ability to produce micro to nano-sized particles with a very narrow distribution within a very short time frame .
Albeit particle size reduction is an effective technique for bioavailability enhancement, stability issue has always been critical for the efficacy of the drug products. In the nanosuspension, drug particles start losing their specific surface area by aggregation due to relatively high surface energy and specific surface area and also for enhanced Brownian motion . For the prevention of aggregation in the wet media and having better stability, polymers and/or surfactants are added to the suspension as stabilizers. These stabilizers provide stability by electrostatic or electrosteric mechanisms . Steric stability provided by the polymer is drug specific. Only few 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 generalized easily . Thus, having a better insight about the polymer properties is very crucial 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 , and controls the drug release during oral administration . Consequently, optimum MW and polymer concentration may help to get the best stabilization performance during and after milling, and faster drug release from the composites.Â Choi et al.  investigated the impact of lower range MW (11,200-49,000 g/mol) of hydroxypropyl cellulose (HW) on itraconazole suspension production and their recovery from the drug composites. In that work, HPC was used solely with the same concentration, and dissolution performance study was absent.Â Sepassi et al.  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.  studied the MW and concentration effect of hydroxypropyl cellulose (HPC) on the dissolution performance of poorly soluble drug griseofulvin (GF) in presence/absence of sodium dodecyl sulfate (SDS) as surfactant. In that investigation, drug nanosuspension was coated and dried on to the surface of pharmatose using fluidized bed technique and also determined the optimum concentration and MW effect of HPC for complete release of the drug particles during dissolution.
To author’s best knowledge, no comprehensive and systematic study has been performed so far 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 combined 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 expected to use minimal amount in the formulation. If only the use of polymer can provide substantial stability in the nanosuspension and immediate release of the drugs in the dissolution from NCMPs, then it is more viable than using surfactant.Â Therefore, this study aims to develop an understanding of the polymer MW and different polymer effect on the physical stability of Itraconazole nanosuspension and drug dissolution from the composites. Itraconazole (ITZ) suspensions were 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, three 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. Dissolution test of the NCMPs were performed by a USP II paddle apparatus.
Itraconazole (ITZ), is an antifungal drug with a water solubility 0.13 mg/L (at pH-7 and 25 Â°C), is a sparingly water soluble drug belong to the BCS Class II was purchased from Jai Radhe Sales (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, ~100, and ~140 kDa molecular weight, respectively, 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 (Midland, MI, USA) and BASF Corporation (Florham Park, NJ, USA) respectively. 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 Âµm (400 Âµm nominal size) was used as the milling media and purchased from Saint Gobain ZirPro (Mountainside, NJ, USA).
Wet Stirred Media Milling (WSMM)
The presuspension (before milling) was prepared following the same procedure used in Afolabi et al. . All the suspension formulations are tabulated below in Table 1. API (Itraconazole) concentration was kept constant at 10% (w/w) and 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 earlier study it was found to be the optimum for fastest and complete drug release from the composite powders.
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 Âµm (nominal size) Zirconia beads, which is the milling media and a screen with 200 Âµm opening was used to hold the beads into the chamber and allowing only the passage of the suspension. A shear mixer (Fisher Scientific Laboratory Stirrer, Catalog No. 14-503, Pittsburgh, PA) was used to prepare the suspension prior to transfer into the holding tank of the miller. The suspension was pumped through a peristaltic pump and was milled under the following conditions: suspension flow rate 126 ml/min, rotor speed 4000 rpm corresponding to a tip speed of 11.7 m/s. To keep the suspension temperature below 35 Â°C, milling chamber and holding tank both were equipped with a chiller (Advantage Engineering Greenwood, IN, USA).Â All the parameters were selected from the earlier work done by Afolabi et al. . To determine the breakage kinetics, particle sizes were measured at different time intervals up to 65 minutes and the suspension were refrigerated at 8 Â°C for one day before spray drying.
Preparation of NCMPs via Spray Drying
The prepared nanosuspesions were dried within a day of milling using a spray dryer (4M8-Trix, Procept, Zelzate, Belgium) running in a co-current flow set up. All the operating conditions were taken from Azad et al. .The suspensions were atomized at 2 bar atomizing pressure using a bi-fluid nozzle 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 Â°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 outlet air stream and collecting them in a glass jar. The dried powders later on were used for powder sample characterization e.g., XRD, DSC, Rodos, and dissolution testing.
Particle Size Analysis
Particle size distributions of the suspensions were measured 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. . During sample addition, intensity was maintained between 40-45% while obscuration was below 8%. Mie scattering theory 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 (medium). Before measuring the PSDs, 2 ml suspension sample was collected 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 placed. To feed the samples, the sample chute was vibrated at 50% settings and 0.1 bar dispersion pressure was imposed to suck in the falling powder through the sample cell of the laser diffraction system.
Determination of Drug Content in the Composite Powders
Drug 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 Âµl is taken 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 morphology and particle size of the ITZ particles before and after milling. SEM images of as-received ITZ and baseline formulation was taken using 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 .
X-ray Powder Diffraction (PXRD)
The crystallinity of the as-received ITZ, physical mixture of ITZ-excipinets, and spray dried powders were analyzed using PXRD (PANalytical, Westborough, MA, USA), provided with Cu KÎ± radiation (Î»= 1.5406 Å). The samples were scanned at a rate 0.165 S-1 for 2Î¸ ranging from 5 to 40Â°.
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 Â°C/min within a range of 25-220 Â°C under nitrogen gas flow. With the help of the integrated software of the machine, melting temperature Tm and fusion enthalpy Î”Hm were determined.
Dissolution 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.Â The dissolution medium was 1000 ml SDS buffer with 3.0 gm/ml concentration at non-sink condition.Â The medium was maintained at 37 Â°C temperature and 50 rpm paddle speed.Â 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 Âµm PVDF membrane type syringe 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 using 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 p<0.0001).
Apparent Shear Viscosity of Milled ITZ Suspensions
The apparent shear viscosity of the nanosuspension was measured by following the procedure from Afolabi et al. , 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 25Â±0.5 Â°C.
Drug nanoparticles formation and physical stability of the milled suspensions
The formulation of the milled drug (ITZ) suspensions are presented in Table 1. Drug (ITZ) nano suspension was first produced in presence of both steric and an anionic surfactant, SDS (Run 1). Due to the synergistic effect of HPC and SDS , Run 1 was used as a baseline to assess 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 . 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 showing 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.
1.Kesisoglou, F., S. Panmai, and Y. Wu, Nanosizing-oral formulation development and biopharmaceutical evaluation. Advanced drug delivery reviews, 2007. 59(7): p. 631-644.
2.Amidon, G.L., et al., A theoretical basis for a biopharmaceutic drug classification: 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. Müller, Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. European Journal of Pharmaceutics and Biopharmaceutics, 2006. 62(1): p. 3-16.
6.Müller, R., C. Jacobs, and O. Kayser, Nanosuspensions as particulate drug formulations in therapy: rationale for development and what 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 water-soluble glyburide. European Journal 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 novel 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 bottom-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.Van Eerdenbrugh, B., G. Van den Mooter, and P. Augustijns, Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. International 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 nanocomminution 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-loaded 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 nanoâ€and microparticles processed 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 Technology, 2011. 4: p. 1-46.
22.Kim, C.-j., Advanced pharmaceutics: Physicochemical principles. 2004: CRC Press.
23.Lee, J., et al., Amphiphilic amino 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.Sepassi, 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 combined 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 Sciences, 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.
Cite This Work
To export a reference to this article please select a referencing stye below: