A review on Pellets - A Drug Delivery System

Bharath Kumar A.; Girendra Kumar Gautam; Syed Salman B.

doi:https://doi.org/10.26452/ijrps.v10i4

A review on Pellets - A Drug Delivery System

Bharath Kumar A. ✉ ¹ , Girendra Kumar Gautam ² , Syed Salman B. ³

1 Research Scholar, Department of Pharmaceutics, Bhagwant University, Sikar Rd, Ajmer – 305 004, Rajasthan, India, +91 9491988545

2 Department of Pharmaceutical Chemistry, Shri Ram College of Pharmacy, Muzaffarnagar – 251 001, Uttar Pradesh, India

3 Department of Pharmaceutics, Mahathi College of Pharmacy, CTM Cross Road, Madanapalle – 517 325, Andhra Pradesh, India

Abstract

Pellets are defined as the spherical or semispherical solid dosages form with the free-flowing property whose size ranges from 500-1500µm. In recent days the pellets are being developed as immediate, modified and controlled release dosage forms due to their enormous range of advantages, i.e. in terms of both technological and therapeutical aspects. In the pelletization technique, fine powder of the active ingredient along with the excipients undergoes agglomeration to produce a small spherical or semispherical solid unit, i.e. pellets. There is various technique for the formulation of the pellet with including drug layering, spray drying and congealing, cryopelletization, hot-melt extrusion and freeze pelletization. The major aim of this paper is to review some general aspects regarding the pellet and pelletization technique like Drug Layering Technique, Spray Drying and Congealing, Cryopelletization, Extrusion Spheronisation, Hot Melt Extrusion, Freeze Pelletization along with their advantages, disadvantages and its application. This review also discussed the evaluation parameter like Shape and surface morphology, and pellets flow property, particle size distribution, porosity, friability, hardness, loss on drying, drug release studies, drug content of pellet, stability studies, moisture content of pellet, drug and excipients compatibility studies, report on the marketed product of pellet and a various patent on pellet.

Keywords

Pelletization, drug layering, spray drying and congealing, cryopelletization, hot-melt extrusion, freeze pelletization

Introduction

Table 1: Advantages and Disadvantages of Pelletization Technique

Therapeutical Advantage	Technological Advantage
1. After the pellet administration, it undergoes free dispersion of the drug in the GIT, which leads to the maximum absorption of the drug from the site of absorption to the systemic circulation.	1. Uniformity in the dose and flow property. 2. Less hygroscopic in nature. 3. This technique can be used for taste masking for unpalatable drugs
2. Decrease the intra and inter variability inpatient. 3. Prevent the dose dumping.	4. Avoids the powder dusting. 5. The efficacy and safety of the drug is enhanced due to the pelletization technique.
4. Prevent the accumulation of the drug in the offsite (Sachan, Singh, & Rao, 2006)	6. The physical appearance of the product can be enhanced by using this technique (Rahman et al., 2009).
Disadvantages of Pelletization Technique
1. The pellets cannot be encapsulated in the capsules since they are rigid in nature which cannot be compressed into a tablet. Since the pelletization technique requires specific equipment for the processing, therefore, this technique is quite expensive.
2. The production process is difficult. (Rowe, 1985; Vuppala, Parikh, & Bhagat, 1997)

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/30aba3a9-45f2-4c74-9fab-1b9933235f1b/image/83083283-d773-48e5-ae5f-9f14ec1a8ebf-upicture1.png — **Figure 1: Different Types of Pelletization Techniques**

The most commonly used techniques are drug layering (Figure 1, Figure 2), spray drying and congealing (Figure 3), cryopelletization (Figure 4), Spheronization (Figure 5, Figure 6), hot-melt extrusion (Figure 7) and freeze pelletization (Figure 8) (Hirjau, Nicoara, & Lupuleasa, 2011) and (Ghai, 2011). This review is discussed about Different Types of Pelletization Techniques and its procedure as shown in Table 2. Evaluation of coated pellets as shown in Table 3. Marketed products of pellets as shown in Table 4. Patent on Pellets as shown in Table 5.

Evaluation of Pellets

Shape and surface morphology

The shape and surface morphology of the enteric-coated pellets are analyzed by using Scanning electron microscopy (SEM) for spherical shape and smoothness by placing a sample on a double-sided carbon adhesive pad and visualized under SEM (Eriksson, Alderborn, Nystrom, Podvzeck, & Newton, 1997).

Flow property

Density

Accurately weigh the pellets (W), and it was passed through by sieve no.40. Weighed pellets are poured into a graduated cylinder, and the volume of the cylinder has to be measured (V_o) for bulk density. Then the cylinder is tapped 100 times and volume have to be measured (V_f) for tap density continued till where two consecutive readings were equal. Bulk density and tap density are calculated by:

\begin{array}{l} B u l k d e n s i t y = \frac{w}{v_{o}} \\ T a p d e n s i t y = \frac{w}{v_{f}} \end{array}

W = Weight of the pellets; V_o = Initial volume of pellets; V_{f =} Final volume of pellets

Angle of repose

The maximum possible angle between the surface of the pile and the horizontal plane is called the angle of repose. It was measured by taking a fixed funnel to certain and pouring the sample pellets to the brim, and it is allowed to flow under the influence of gravity; after forming a sharp edge of the pile, the radius of pile and height of pile has to be measured and angle of repose is evaluated by the given formula,

θ = \tan^{- 1} (\frac{h}{r})

θ = angle of repose; h = height of the pile; r =radius of pile

* Angle of repose ˂25-30⁰ indicates excellent flow property of pellets.

Table 2: Different Types of Pelletization Techniques and its procedure

S. No.	Technique	Procedure
1.	Drug Layering Technique Powder Layering Suspension or Solution Layering	Drug layering involves the deposition of a layer of drug moiety from the suspension, drug powder or through the solution over the core, which may be a granule or crystal (made up of the same material or inert in nature)
		Suspension or Solution Layering Solution or suspension is prepared, which consist of uniformly dispersed drug and other excipients moieties. The dissolved moiety crystallizes by forming a solid bridge between the core and the initial layer of the drug substance. This process is continued till a desired layer of the drug or polymer is obtained (Zimm, Schwartz, & Connor, 1996)

		Powder Layering The dry drug powder and the other components are deposited over the starting core by using the liquid binder. Crosslinkage between the core and dry drug powder takes place through a liquid bridge which is replaced by the solid bridge eventually (Pearnchob & Bodmeier, 2003)

		Disadvantage of Layering Technique In this technique, a low quantity of the drug is loaded, which is not suitable for high dose drugs. The final composition of the resultant pellet may vary if spray loss occurs (-Sellassie & Knoch, 2002).

2.	Spray Drying and Congealing	Spray Drying Suspension or solution of the drug is prepared with or without excipients. The solution is sprayed in the hot stream of air. As the droplets come in contact with the hot air, evaporation of the medium take place, and it is continued until the entire application medium is evaporated. Which results in the formation of highly spherical particles (Celik & Wendel, 2005).

		Spray Congealing Drug is melted. The melted drug is dispersed in the hot melt of gums, fatty acid or waxes. The resulted slurry is sprayed into the air chamber. The temperature of the chamber should be kept below the melting point of the formulation component, which results in the production of the spherical congealed pellet (Atilla & Suheyla, 1994).

3.	Cryopelletization	In this technique, the liquid formulation containing the drug is converted into solid particles or pellets by using liquid nitrogen at -160ºC (Ratul & Baquee, 2013). The equipment used for crypelletization consists of a container with perforated plates, reservoir, conveyor belt with transport baffles to the storage container.
		Initially, the liquid formulation is converted into droplets by using the perforated plates. The resultant droplet from the perforated plates fall in the liquid nitrogen that is present below the plate, and the droplets freeze immediately. The frozen droplets or pellets are taken out from the liquid nitrogen and transported to the storage container at -600 ºC before drying. The pellets are dried by using the freeze dryer (Weyermanns, 1997).

4.	Extrusion Spheronisation	The major objective of this technique is to produce uniformly sized pellets or spheroid which is having a high drug loading capacity. This technique includes the following steps:-
		Dry mixing In this process, the dry powder blend is prepared, which consist of the active ingredient and excipients by using the mixers like the planetary or high shear mixer (Harrison, Newton, & Rowe, 1984).
		Wet mixing The above-obtained powder blend is mixed with a liquid binder to produce a wet mass by using the planetary mixer.
		Extrusion In the extrusion process, the wet mass is shaped into the cylindrical segment or the extrudate of uniform diameter. The above process is carried out by using various extruders like piston feed, screw feed and gravity feed extruders [Figure 4]. In this process, the pressure is applied across the wet mass until it passes through the calibrated screen or die opening, which results in the formation of the cylindrical extrudate (Steckel & Mindermann-Nogly, 2004).
		Spheronisation stage The obtained cylindrical segment or extrudate are broken down into solid spheres or spheroids.
		Drying of spheroids The obtained spheroids can be dried either at room temperature or at an elevated temperature by using a drier like a tray, oven or fluidized drier (Breitenbach, 2002).
		Screening Screening is carried out for the production of uniformly sized pellets or spheroids and to avoid the pellets with a high size polydispersity index (Gandhi, Kaul, & Panchagnula, 1999).

5.	Hot Melt Extrusion	This technique is the upgrade version of the extrusion and spheronization method; in this methodology, the excipients and the active ingredient are converted into the semi-molten or molten state. The molten or semi-molten mass is converted into pellets or solid spheres by using a suitable apparatus. The main advantage of this method is that it does not require a lengthy drying process since no additional solvent like water or other solvent is added for the granulation process (Wong, Cheong, & Heng, 2005).
		Advantage No solvent or water is used during any process of the technique. There is no need of drying the resultant pellet, and processing steps are short. Uniform dispersion of the drug takes place over the solid support. Resultant pellets exhibit good stability.
		Disadvantage This technique utilizes a larger amount of energy.This technique is not applicable for heat sensitive drugs (Amita et al., 2015).

6.	Freeze Pelletization	In this technique, the drug is dispersed into the molten solid carrier; the resultant mixture is introduced in the form of a droplet into a column containing immiscible inert liquid. In respect to the density of the liquid in the column, the droplet can move either in the upward or downward direction. Later the droplets are solidified into the solid sphere or droplets The major advantage of this method is that the drying process of the pellet is not required since the solid carrier used is remain solid at room temperature

		Ideal Characteristic Features of Carrier used in the Pelletization The carrier may be hydrophilic or hydrophobic in nature. It should be solid at the room temperature. The melting point should be less than 100ºC (Cheboyina & Wyandt, 2008).

		Equipment Used Freeze pelletizer I Freeze pelletizer II (Wyandt & Cheboyina, 2008).

		Freeze Pelletizer I Carrier is introduced through the upper portion of the column. The density of the carrier is greater as compared to the density of the liquid in the column. Carrier is solidified at the bottom of the column. A hydrophilic carrier like polyvinyl alcohol or polyethylene glycol. Liquid for the column used are of low-density oil such as mineral oil or vegetable oil.

		Freeze Pelletizer II Carrier is introduced through the lower portion of the column. The density of the liquid in the column is greater as compared to the density of the solid carrier. Carrier is solidified at the top of the column. A hydrophobic carrier like glyceryl behenate or glyceryl monostearate. Liquid for the column used are of high-density hydrophilic liquid such as polyethylene glycol or ethyl alcohol.

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https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/30aba3a9-45f2-4c74-9fab-1b9933235f1b/image/a8e83ea5-5ed3-4f23-a000-39330d1a74f1-upicture3.png — **Figure 3: Schematic Representation of Spray Drying and Congealing**

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/30aba3a9-45f2-4c74-9fab-1b9933235f1b/image/8621f45c-2031-433b-986e-95627f19e238-upicture4.png — **Figure 4: Schematic Representation of Cryopelletization**

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/30aba3a9-45f2-4c74-9fab-1b9933235f1b/image/5d6d7f65-7164-425a-9cf2-af39366b47a0-upicture5.png — **Figure 5: Schematic Representation of Extrusion Spheronization**

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/30aba3a9-45f2-4c74-9fab-1b9933235f1b/image/0cbbdeed-9db2-413f-ad97-82c0fb7bf48e-upicture6.png — **Figure 6: Schematic representation of spheronization process**

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/30aba3a9-45f2-4c74-9fab-1b9933235f1b/image/2ddf5c9d-31af-4d7a-ac14-16f786bd1b39-upicture7.png — **Figure 7: Schematic representation of hot melt extrusion**

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/30aba3a9-45f2-4c74-9fab-1b9933235f1b/image/86f9fb00-cd8e-48e0-99b2-e710822a175f-upicture8.png — **Figure 8: Schematic representation of freeze pelletization**

Table 3: Evaluation of coated pellets

S. No.	Parameter	Method used	Instrument	References
1.	Shape and surface morphology	Microscopy	Scanning electron microscopy (SEM)	(Kovacevic, Mladenovic, Djuris, & Ibric, 2016)
2.	Flow property	a. Bulk density and Tap density	Automated tapper, Fixed funnel	(Rana et al., 2018; Rupam, Wagh, Rajendra, & Surawase, 2020)
3.	Size distribution	Sieve analysis	Laser diffraction	(U S Pharmacopeia, 2007)
4.	Porosity	Pore Sizer	Mercury porosimetry	(Dukic-Ott et al., 2008)
5.	Friability	Weighing	Roche friabilator	(Kuang et al., 2017)
6.	Hardness	Crushing force	Texture analyzer	(Aulton & Taylor, 2007)
7.	Loss on drying	Gravimetry method	Halogen moisture analyzer Mettler-Toledo HR 83	(Lustig-Gustafsson, Johal, Podczeck, & Newton, 1999; Stefanic, Vrecer, Rizwal, Mrhar, & Bogataj, 2014)
8.	Drug release studies	Invitro studies	USP apparatus-II	(Debunne, Vervaet, Mangelings, & Remon, 2004; Lustig-Gustafsson et al., 1999)
9.	Drug content	Assay	HPLC	(Debunne et al., 2004; Stefanic et al., 2014)
10.	Stability	Shelf life	Humidity cabinet	(Kranz & Gutsche, 2009; Li et al., 2018)
11.	Moisture content	Titration	Karl Fischer	(Scott et al., 2020; Shravani, Lakshmi, & Balasubramaniam, 2011)
12.	Drug and excipients compatibility studies	a. Spectral analysis	a. FTIR	(Eriksson et al., 1997; Stefanic et al., 2012)

Table 4: Report on marketed products of pellets

S. No.	Marketed product	Active drug	Company and Manufacturer	Therapeutic class
1.	Testopel pellets	Testosterone	Slate pharma.	Steroid
2.	Omeprazole delayed-release capsules	Omeprazole	Remedy repack Inc.	Anti-ulcer
3.	Itraconazole enteric coated pellets	Itraconazole	Titan pharma. (India) Pvt. Ltd.	Antifungal
4.	Antra MUPS	Omeprazole	Astra Zeneca	Anti-ulcer
5.	Prevacid Solutab	Lansoprazole	Novartis	Anti-ulcer
6.	Losac MUPS	Omeprazole magnesium	Astra Zeneca	Anti-ulcer
7.	Crymbatla	Duloxetine hydro chloride	El Lilly and company	Antidepressant
8.	Theodur	Theophylline	Key	Anti asthmatic
9.	Toprol XL	Metoprolol tartrate	Astra Zeneca	Antihypertensive
10.	Esomeprazole	Esomeprazole magnesium	Astra Zeneca	Anti-ulcer
11.	EC-Naproxen	Naproxen	Woodward pharma	Anti-inflammatory

Table 5: Report on Patent on Pellets

S. No.	Title	Author	Publication number	Publication year
1.	Enteric-coated Zinc-oxide pellets	Li Fengxian, Shao Yongjie, Wu Bing, Zhuang Wanlong	CN106260599A	2016
2.	The aqueous enteric coating composition	Obara Sakae, Quadir Anisul	WO2016182737A1	2016
3.	Lansoprazole enteric-coated capsule and preparation method	Guo Yanli, Hu zhumei, Xia Tong, Zhang Yunsheng	CN106361725A	2017
4.	Tandospirone enteric-coated minipill and preparation and application there of	Chen gang, Li Xiaoli, Lia Liping, Wang Ping, Zhao Sijiang	CN106344519A	2017
5.	S- carboxymethyl-L-Cysteine enteric pellet capsule	Pei Zejian, Wang Jiansong, Wang Wei, Xiao Ying, Zhu Shaoxuan	CN108338978A	2018
6.	Esomeprazole magnesium enteric-coated pellet and preparation method	He Jianxing, Sun Jianmin, Sun Wei, Yin Renjie	CN107625736A	2018
7.	Compound recipe omeprazole enteric-coated capsules and preparation method thereof	Hou Wen Zhang Alqin	CN110478333A	2019
8.	Omeprazole enteric capsule and preparation method	Chen Xinmin, Feng Weixia, Huang Junpeng, Mo Zeyi, Qi Honglin, Xie Bin, Xu Wei, Yang dong, Yang Liuzeng, Zhang Jianming	CN109125282A	2019
9.	Omeprazole enteric-coated pellets and production thereof	Cheng Yan, Huang Xin, Liang Fengyan, Liang Zhijun, Zeng Sheng, Zhang Kun, ZhangbYongqian	CN111481525A	2020
10.	Procedure for preparing enteric-coated pellets containing a proton pump inhibitor and multi-particle pharmaceutical compositions containing them	Atilio Los Mario	US10786458B2	2020

Carr’s index

Carr's index (%) =

\frac{ρ_{t a p p e d d e n s i t y} - ρ_{b u l k d e n s i t y}}{ρ_{t a p p e d d e n s i t y}} \times 100

* Carr’s index = ˂10% indicates excellent flow property.

Hausner’s ratio

H a u s n e r' s r a t i o = \frac{ρ_{t a p p e d d e n s i t y}}{ρ_{b u l k d e n s i t y}}

*Hausner’s ratio = 1.00-1.11 indicates excellent flow property (Trivedi, Rajan, Johnson, & Shukla, 2007).

Size distribution

Size distribution studies of pellets were carried out by mechanical sieve shaker with sieve no's (18, 20 24). In this, sieves are arranged in an ascending manner of 18, 20, 24 and receiving pan is placed below the sieve no. 24. Place 100mg of sample in the sieve no.18. Then sieve stack is set up into the mechanical shaker and operated for 10mins. After 10mins the sieve stack is removed from the shaker and weighed individual sieve with retained sample (Turkoglu, Varol, & Celikok, 2004).

The formula for the percentage of sample retained in each sieve:

% R e t a i n e d = \frac{M a s s r e t a i n e d i n e a c h s i e v e}{T o t a l m a s s o f s a m p l e}

The formula for the percentage of sample passed from each sieve:

% p a s s i n g = 100 - % r e t a i n e d

Porosity

Porosity has an influence on coating, flow property of pellets and packing. Mercury porosimetry (207MpA) measure the “pore sizer” (volume of distribution of pores approximately from 3nm -200µm) in the pellets. Pores are analyzed qualitatively by SEM and quantitatively by mercury intrusion or extrusion method. Pellets are previously dried in an oven at 40⁰c for about 72 hrs to reduce the moisture and residual water content present in the pellets. A sample size of 0.7-1.7g was taken into the Autopore III sampler and evacuated to 6.61Kpa, followed by being subjected to low pressure of mercury filling (3.4-193Kpa) and high pressure of mercury filling (6.193-71Mpa). Mercury has a high surface tension it can influence the minimal surface area and large radius by forming contact with the solid, making a curvature to possible at a given pressure. While in the high-pressure mercury intrusion causes imbalance between the surface tension and surface area leads to a radius of curvature of mercury contact with solid becomes smaller. When the radius is equal to the pore entrance, mercury is forced to fill the volume by applying external pressure (Xu et al., 2021).

Friability

Friability of pellets were carried out by Roche friabilator. Initially weighed 10g of pellets (W₁) and taken into the drum of friabilator operated for 10 minutes. With 25RPM, again reweigh the pellets with the removal of fines and calculate the weight loss by percentage friability.

The percentage friability should not be more than 1%.

% P e r c e n t a g e f r i a b i l i t y = \frac{(W_{2} - W_{1})}{W_{1}} \times 100

W₁ = Initial weight of pellets

W₂ = Final weight of pellets

Hardness

In each batch, 10 pellets are tested for hardness by using crushing force with speed to perforce of 1mm/min, speed of 10mm/min during the test (Surekha, Venugopalaiah, Prakash, & Gobinath, 2013).

Loss on drying

1gm of pellets are weighed, note it as S₁ and placed in a Petri plate. Then subject to heating in an oven at 105⁰C about 3hrs. After 3 hours, the petriplates are reweighed, note it as S₂ and calculate the percentage of weight loss on drying.

P e r c e n t a g e l o s s = \frac{S_{2} - S_{1}}{S_{1}} \times 100

S₁ = Initial weight of pellets before drying

S₂ = Final weight of pellets after drying

Drug release studies

In-vitro drug release studies

Dissolution is the process by which a solid substance enters into the solvent to form a solution. Dissolution studies are the rate of drug release before it being absorbed in the gastro intestinal tract (GIT).

Invitro dissolution study was carried out by the non-compendia flow-through system consisting of magnetic stirrer with a heater to a peristaltic pump, and it is inserted into a silicon tube of middle position, and it is immersed into a dissolution cell containing 0.01M HCl.

The rotation of the stirrer should be 80RPM, and the temperature of the medium is 37⁰C. Later, HCl is replaced with a phosphate buffer of pH of 6.8. The sample is placed in the dissolution cell, and at every 3 residence times, 10µl sample have to be drawn and estimate drug release by Agilent 1100 series HPLC method.

Drug content

HPLC assay

The amount of drug is released, and drug content are assayed by HPLC method using UV detector of range 275nm. Mobile phases are 45% Acetonitrile/55% potassium biphosphate with a flow rate of 10.5ml/min.

Acetonitrile, Water, Triethylamine in the 40:60:1 are used as standards. 10µl volume of sample from dissolution cell has to be filtered in the 0.45µm Millipore filter (pH10) and then injected in the HPLC.

Stability

Pellets were stored in a humidity cabinet for 1 month at 40 ± 20⁰C and 75%± 5 RH. Pellets are stored in brown glass bottles in two manners with a desiccant (S series) and without desiccant (F series) at every 1^st, 2^nd, 3^rd month up to 6 months.

Drug content was analysed in dissolution studies and degradation by HPLC (Kumar, Muthukumaran, & Chenchuratnam, 2012).

Moisture content

Moisture content in the pellets were determined by the Karl Fischer titration method, in which 3g of the sample has to be taken and crushed using motor & pestle, from that 0.2g (w) of the sample was taken into the titration vessel containing 35ml of methanol and titrate against Karl Fischer titration reagent till to endpoint then moisture content was determined by using the following formula,

Moisture content (%w/w) =

(F B r - I B r) K a r l F i s c h e r f a c t o r \times 100 / w \times 100

FBr = Final burette reading

IBr = Initial burette reading

W = Weight of the sample taken for titration

Drug and excipients compatibility studies

Spectral analysis

Drug and excipients compatibility was determined by spectral analysis in FTIR in the range of 4000-400cm^-1. For spectral analysis, samples of pellets are subjected to drying to remove the moisture content and mixed with potassium bromide for trituration using motor and pestle and then analyze the compatibility in infrared spectra.

Thermal analysis

Interaction of drug and polymer is analysed by DSC (Differential Scanning Calorimetry), in which 2g of pellets are subjected to heating in a crimped aluminium pan at 40-400⁰C in the range of 10^0C/min to maintain the inert atmosphere nitrogen gas is purging in the analysis in the range of 40ml/min.

X-ray diffraction

Polymeric natures of pellets were determined by X-ray diffraction spectrum using X-ray diffractometer having radiation of copper-potassium α radiation of 40Kv, 30mA (Sangram et al., 2017; Susmit et al., 2018).

Conclusion

In this review, we have concluded that absorption and oral bioavailability of enteric-coated pellets with controlled, modified and sustained released dosage form which was formulated by different techniques such as cryopelletization, extrusion methods, spray drying and congealing followed by advantages and drawbacks. In formulation, the pellets are coated and compressed for sustained release and gastric resistant. The formulated pellets can be evaluated by friability, surface morphology, invivo and in-vitro studies to resist the pH-dependent in acidic media of GIT and sustained release.

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