CELLETS® 700

(700-1000 µm)

CELLETS® 700 is a subtype of pellets made of microcrystalline cellulose. The size ranges from 700 µm to 1000 µm. Find more product information and technical specifications.

Abstract

Pellets are one of multiparticulate pharmaceutical forms and can offer numerous technical and biopharmaceutical advantages compared with single dose unit formulations, e.g. tablets and capsules. This study aimed at formulation of controlled-release pellets of doxazosin mesylate (DM), a widely used treatment for antihypertensive and benign prostatic hyperplasia. DM was loaded onto microcrystalline cellulose CELLETS® pellets using hydroalcoholic solution and alcoholic suspension layering techniques to achieve a minimum drug load of 4 mg DM/g pellets. DM-layered CELLETS were coated by Aquacoat dispersion (ready-made ethylcellulose dispersion) using a coating pan technique as a simple and widely utilized technique in pharmaceutical industry. Controlled-release DM-layered pellets showed a release profile comparable to the controlled-release commercial product Cardura® XL Tablet. Also, the mechanism of DM release from Aquacoat CELLETS® was mathematically modeled and imaged by scanning electron microscopy to elucidate drug release mechanisms from the prepared pellet formulations. Accelerated stability studies of the prepared pellets were performed under stress conditions of 40 °C, and 75 % RH for 3 months. In conclusion, preparation of controlled-release DM-layered CELLETS® is feasible using a simple and conventional coating pan technology. Read more about controlled-release doxazosin mesylate pellets.

References

H. A. Hazzah, M. A. EL-Massik, O. Y. Abdallah & H. Abdelkader, Journal of Pharmaceutical Investigation (2013), 43:333–342. doi:10.1007/s40005-013-0077-0

Additional information

CELLETS® are perfect starter beads for coating and layering of API, such as doxazosin mesylate. Multilayer formulation attempts enable defined release profiles and improved bioavailability. Check different pellet sizes from 100 µm to 1400 µm which fit to your formulation.

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Contact our partner Glatt Pharmaceutical Services!

Pore Former basic drugs

Abstract

Bioavailability of weakly basic drugs may be disrupted by dramatic pH changes or unexpected pH alterations in the gastrointestinal tract. Conventional organic acids or enteric coating polymers cannot address this problem adequately because they leach out or dissolve prematurely, especially during controlled release applications. Thus, a non-leachable, multifunctional terpolymer nanoparticle (TPN) made of cross-linked poly(methacrylic acid) (PMAA)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) was proposed to provide pH transition-independent release of a weakly basic drug, verapamil HCl (VER), by a rationally designed bilayer-coated controlled release bead formulation. The pH-responsive PMAA and cross-linker content in the TPN was first optimized to achieve the largest possible increase in medium uptake alongside the smallest decrease in drug release rate at pH 6.8, relative to pH 1.2. Such TPNs maintained an acidic microenvironmental pH (pHm) when loaded in ethylcellulose (EC) films, as measured using pH-indicating dyes. Further studies of formulations revealed that with the 1:2 VER:TPN ratio and 19% coating weight gain, bilayer-coated beads maintained a constant release rate over the pH transition and exhibited extended release up to 18 h. These results demonstrated that the multifunctional TPN as a pHm modifier and pH-dependent pore former could overcome the severe pH-dependent solubility of weakly basic drugs.

Introduction

Many existing active pharmaceutical ingredients (APIs) (drug compounds) are either weak acids or weak bases; their water solubility can change significantly with the lumen pH changes along the gastrointestinal tract (GIT) as a result of variation in the ionization degree. Severe pH-dependent solubility could pose a great challenge to achieving consistent and predictable performance of oral dosage forms, as abrupt changes in release rate may result in unexpected dissolution, absorption, and bioavailability of the drug, leading to increased risks of adverse side effects or decreased therapeutic efficacy. This problem may be pronounced for weakly basic drugs with low solubility at high pH, especially those with a narrow therapeutic index, or requiring prolonged release, because in the lower GIT the pH is >6.8 [1]. Furthermore, food intake, disease state (e.g., inflammatory bowel disease, gastritis, colitis), concomitant medication (e.g., proton pump inhibitors), and inter- and intra-individual variations, among other factors, can alter the pH in the GIT, which deviates from the pH of simulated gastric and intestinal fluid for in vitro testing and prediction [2,3,4]. Hence, novel strategies to formulate weakly basic drugs with extreme pH-dependent solubility in controlled release forms could enhance the repertoire of advanced medications available to patients.
To compensate for the varying pH values in the GIT, several approaches have been employed. One approach is the addition of small-molecule pH modifiers to the immediate vicinity of the drug to change the microenvironmental pH (pHm), thus enhancing the drug solubility. For example, organic acids (e.g., adipic, fumaric, and succinic acids) have been introduced into formulations of weakly basic drugs, reducing the pHm sufficiently, thereby facilitating drug dissolution, irrespective of the pH of the bulk solvent [5,6,7,8,9,10,11]. Drug release will depend on the compatibility of the organic acid with the drug in terms of the buffering capacity of organic acids and the pKa of the drug. Nevertheless, the incorporation of organic acids remains challenging as they are prone to leach out from the formulation, leading to inefficient pH modulation over time [12]. Therefore, large amounts of organic acids are required in order to achieve prolonged pH-independent drug release [5,13], which often makes this approach inadequate for controlled release formulations.
Another approach to compensate for the reduction in drug solubility is the use of enteric coating polymers on tablets, pellets, or beads as permeability modifiers, which can increase drug permeability at higher pH. In such coatings, polymers with pH-dependent solubility or swellability are employed, either alone or incorporated in a hydrophobic polymer (e.g., ethylcellulose (EC)) that acts as a membrane barrier to drug diffusion, resulting in slowed drug release. For example, methacrylic acid–ethyl acrylate copolymer (Eudragit® L) and hydroxypropyl methylcellulose acetate succinate are frequently incorporated into these membranes as pore forming materials for pH-dependent release [13,14,15,16,17,18,19,20,21,22,23]. At a pH above their pKa’s, the pore formers dissolve and leach out of the membrane film to form channels that facilitate drug diffusion. However, as pore formers leach out, the film becomes more porous and weaker, increasing the risk of dose dumping due to weakened structure or ruptures of the coating [24].
Recent advances using biopolymer-based nanomaterials, molecular imprinted polymers, and mathematical and computational models have been used to address the various challenges of drug delivery systems [25,26,27,28,29]. Biopolymers such as starch, collagen, chitosan, etc., are useful for their biocompatibility, biodegradability, and ease of synthesis and modifications [25]. Controlled release dosage forms capable of being flexible, releasing drugs in a timely manner, with desired duration and dosage, are more important than ever, and mathematical and computational models also function as influential tools in addressing the potential mechanisms or impediments of drug delivery systems [26,27,28,29].
Previously, a crosslinked terpolymer nanoparticle (TPN), consisting of poly(methacrylic acid)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) [30,31,32,33], was incorporated into ethylcellulose films (TPN-EC) to respectively reduce or enhance the permeability of the film coating by a pH-dependent shrinking (at low pH) and swelling (at high pH) mechanism [34]. Unlike other soluble polymeric pore-formers, the TPN did not increase the viscosity of EC dispersions for coating, attributable to its crosslinking structure [31,32,33]. For the same reason, TPN did not leach out from cast TPN-EC films, maintaining good mechanical properties compared to conventional Eudragit® L-EC films. When used as a membrane coating over beads loaded with a water-soluble drug, diltiazem HCl, TPN-EC provided faster drug release at pH 6.8 than at pH 1.2 [34]. The biocompatibility of TPN was demonstrated previously in vitro using isolated rat hepatocytes [32].
Inspired by previous findings regarding the pH-dependent properties of TPN, in this work, we explore the application of TPN for the first time to develop an advanced, controlled release bilayer-coated bead formulation for weakly basic drugs that exhibits severe pH-dependent water solubility. Verapamil HCl (VER) was selected as a model drug because it undergoes extreme decrease in solubility by several orders of magnitude when the media pH is increased from acidic to neutral and weakly basic conditions [9,35]. By exploiting the pH-dependence of TPN, we proposed that an increase in permeability at high pH could help compensate for the low solubility of the drug in its unionized form, thereby permitting a constant release rate when transitioning from gastric to intestinal pH. Additionally, we explored the ability of TPN to serve as a pHm modifier, owing to the presence of its acidic functional groups in MAA. Because TPN is retained within EC, unlike traditional leachable pHm modifiers when formulated together with the drug in a matrix, the source of the acidifying agent could be sustained throughout dissolution, while preserving dosage form integrity.
To investigate the effectiveness of combining both the permeability and the pHm modulation strategies of TPN, experiments were performed using EC matrix free-films incorporated with VER and TPN (VER-TPN-EC) and a bilayer-coated bead design consisting of an inner VER-TPN-EC matrix, surrounded by an outer membrane composed of TPN-EC. As illustrated in Figure 1, the TPN composition was first adjusted by varying the amounts of the pH-responsive monomer, MAA, and cross-linker, N,N′-methylenebis(acrylamide) (MBA) for pH-dependent swelling (medium uptake) and drug release via experiments using composite free-films. The best-performing TPN-containing films were then tested for their ability to lower pHm. Subsequently, the TPN was incorporated into a bilayer-coated bead design, where it was expected to lower the pHm in the matrix layer and regulate permeability in the membrane layer by its pH-dependent swelling. The effects of formulation parameters such as VER:TPN ratio within the matrix layer and membrane coating level on the pH-independence of dissolution rate in various pH conditions were evaluated.
Figure 1. A flow chart of the optimization strategy to achieve pH transition-independent controlled release of VER from a TPN-containing bilayer-coated beads. Formulation strategy for TPN bilayer-coated beads containing weakly basic VER Optimization of TPN composition to achieve pHm modification and pH-dependent swelling, followed by strategic placement of TPN in the bilayer bead matrix and membrane layers are proposed to overcome pH-dependent solubility of VER. Figure created with BioRender.com (accessed on 15 December 2022).
Our cumulative research investigating the various applications of TPN (e.g., nanoparticle drug carrier in injectables, enteric coating agent and pore former in film coatings, recrystallization inhibitor in amorphous solid dispersions) is helping us widen the breadth of its capabilities. Namely, in the present research, the ability of TPN for pHm modification, pH-responsive swelling, nanoscale pore formation, interaction with drugs, and non-leachability comprise a set of multi-faceted features that set it apart from traditional excipients, which could improve the efficacy and quality of controlled release dosage forms for weakly basic drugs. As the landscape of new drug molecules continues to shift towards greater challenges (e.g., poor solubility, pH-dependent solubility, narrow therapeutic index, etc.) the need for more advanced, multifunctional excipients can be expected to increase.

Materials and Methods

2.1. Materials

Soluble corn starch, methacrylic acid (MAA), N,N′-methylenebisacrylamide (MBA), sodium thiosulfate (STS), potassium persulfate (KPS), sodium dodecyl sulfate (SDS), and sodium phosphate tribasic were purchased from Sigma Aldrich (Oakville, ON, Canada). Verapamil HCl (VER) was purchased from Spectrum Chemicals, (New Brunswick, NJ, USA). Hydrochloric acid (HCl) was purchased from Caledon (Georgetown, ON, Canada). SNARF-4F (#S23920) was purchased from Fisher Scientific (Ottawa, ON, Canada). Bromocresol green was purchased from Sigma Aldrich (Oakville, ON, Canada). Ethylcellulose (Surelease® E-7-19040) was kindly donated by Colorcon (West Point, PA, USA). Polyvinylpyrrolidone (PVP) (Kollidon®/PVPK30) was kindly donated by BASF (Ludwigshaven, Germany). Polysorbate 80 (Tween 80-LQ-(CQ)) was kindly donated by Croda (Edison, NJ, USA). Microcrystalline cellulose (MCC) beads ([…] annotation from the publisher: for example: CELLETS® 700) were used as the coating substrate […].

Conclusions

In this work, the multifunctionality of a nanogel TPN was investigated as a non-leachable pHm modifier and pH-responsive pore former in a bilayer-coated bead formulation for the pH transition-independent controlled release of weakly basic drugs. The results demonstrated that incorporation of TPN, comprised of pH-sensitive MAA and cross-linker MBA, enables the inner matrix layer of VER-TPN-EC to maintain a pHm approximately 1.5 unit lower than the external buffer pH, which may be further enhanced by coating with a TPN-EC membrane. In a simulated gastric and intestinal pH transition condition (i.e., from pH 1.2 to 6.8), the bilayer-coated beads with 16% to 19% WG resulted in a constant release rate during the pH transition, followed by a sustained release of VER up to 18 h, beyond the extent achieved when tested in single pH media. This ability to overcome the poor solubility of VER at high pH can be ascribed to the combinatory effects of the pH-dependent swelling of TPN that increased permeability, preferred retention of protons in the TPN due to Donnan equilibrium, pH-dependent complexation between MAA and VER, and the barrier to diffusion of buffer ions by the outer coating. This work suggests that the multifunctionality and tunability of TPN-EC formulations and the formulation design strategy may be expanded to tackle the challenges faced by other drugs with severe pH-dependence of water solubility.

Disclaimer

Excerpt from: Pharmaceutics 2023, 15(2), 547; https://doi.org/10.3390/pharmaceutics15020547. by Hao Han R. Chang, Kuan Chen, Jamie Anne Lugtu-Pe, Nour AL-Mousawi, Xuning Zhang, Daniel Bar-Shalom, Anil Kane, and Xiao Yu Wu.

References

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Benefits of multilayer high drug-loaded amorphous solid dispersions

Introduction on amorphous solid dispersions

What is the benefit of multilayer amorphous solid dispersions? Recently, several studies had been performed on amorphous solid dispersions working spheres or starter beads. Starter beads, such as MCC (Microcrystalline Cellulose) spheres are employed due to their high friability and chemical inertness. Some studies are even working on solventless pelletization and amorphization using high shear granulator techniques [1].

Amorphization of poorly water-soluble drugs is a promising approach to improve the solubility and dissolution rate as amorphous solids lack a crystal lattice with long-range order [2]. Unfortunately, a high chemical potential compared to crystalline forms makes amorphous forms thermodynamically unstable. Thus, amorphous drugs exhibit low physical stability and finally lack of recrystallization [3,4]. In turn, surface crystallization is to be minimized.

Multilayer amorphous solid dispersions

This is the key focus of a publication by Eline Boel and Guy Van den Mooter: They had been investigating a promising solution of multilayer high-drug load amorphous solid dispersions, as follows [5]:

Inhibiting surface crystallization is an interesting strategy to enhance the physical stability of amorphous solid dispersions (ASDs), still preserving high drug loads. The aim of this study was to investigate the potential surface crystallization inhibitory effect of an additional polymer coating onto ASDs, comprising high drug loads of a fast crystallizing drug, layered onto pellets. For this purpose, bilayer coated pellets were generated with fluid-bed coating, of which the first layer constitutes a solid dispersion of naproxen (NAP) in poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in a 40:60 or 35:65 (w/w) ratio, and ethyl cellulose (EC) composes the second layer. The physical stability of these double-layered pellets, in comparison to pellets with an ASD layer only, was assessed under accelerated conditions by monitoring with X-ray powder diffraction (XRPD) at regular time intervals. Bilayer coated pellets were however found to be physically less stable than pellets with an ASD layer only. Applying the supplementary EC coating layer induced crystallization and heterogeneity in the 40:60 and 35:65 (w/w) NAP-PVP-VA ASDs, respectively, attributed to the initial contact with the solvent. Caution is thus required when applying an additional coating layer on top of an ASD layer with fluid-bed coating, for instance for controlled release purposes, especially if the ASD consists of high loads of a fast crystallizing drug.

Read more on doi:10.1016/j.ijpharm.2022.122455.

How about following up studies on ASD formulation with starter beads? Simply, contact us für MCC spheres, such as CELLETS® 700 (700-1000 µm, US mesh 18/25).

Your technology and formulation partner for amorphous solid dispersions:

Glatt in amorphous solid dispersions

References

[1] K. Kondo, T. Rades, European Journal of Pharmaceutics and Biopharmaceutics 181 (2022) 183–194 doi:10.1016/j.ejpb.2022.11.011

[2] B.C. Hancock, M. Parks, Pharm. Res. 17 (2000) 397-404.

[3] L.I. Blaabjerg, E. Lindenberg, T. Rades, H. Grohganz, K. Lobmann, Int. J. Pharm. 521 (2017) 232-238.

[4] A. Singh, G. Van den Mooter, Adv. Drug Deliv. Rev. 100 (2016) 27-50.

[5] E. Boel, G. Van den Mooter, International Journal of Pharmaceutics (2022) 122455. doi:10.1016/j.ijpharm.2022.122455

 

Abstract

This case study is a short abstract on spouted bed characteristics, following closely findings in the publication by J. Vanamu and A. Sahoo [1].

Spouted bed systems are of highest importance for all powder processing industries, and more specific in pharmaceutical industry for coating and drying in pellet technologies [2]. These systems offer manufacturing particularly fine and temperature-sensitive particles from small to large scale: laboratory systems are capable of processing product volumes of very few grams, while production systems can handle capacities of several tons [3].

But how to control conditions in spouted beds for efficient process applications, like mixing, coating, or drying?

There might be certain reasons, that the hydrodynamic behavior of the spouted bed in the pharmaceutical industries is less investigated. The referred publication shed some light on the hydrodynamic characteristics of a spouted bed where the MCC Spheres (CELLETS®) are adopted as the bed material. These starter cores are ideal model systems due to their perfect sphericity and zero-level friability. At the same time, smooth and defined surface structure initiate perfect modelling conditions in the spouted bed dynamics.

Material

CELLETS®, made of 100% Microcrystalline Cellulose, have been used as bed material. The physical properties of the CELLETS® are shown in Table 1. The CELLETS® particle morphology is represented in Figure 1.

Parameter Value
CELLETS® 700 and CELLETS® 1000
Size distribution 700-1000 µm (CELLETS® 700)

1000-1400 µm (CELLETS® 1000)

Bulk density 800 kg/m3
Particle sphericity > 0.9
Void fraction 0.42
Geldart classification B

Table 1: Physical properties of the CELLETS®.

SEM micrographs of CELLETS® 700

Figure 1: SEM micrographs of CELLETS® 700, found in [1].

Spouted bed: experiment setup

There are some international players on the market of spouted bed technologies, such as Glatt which seems to be the major one (Figure 2). In this framework, a self-made setup is used for experiments. The experiments that have been carried out in a column, which is fabricated from a Perspex sheet. This column consists of a cylindrical section of height 0.53 m and a diameter of the cylinder of 0.135 m. The column further converged the diameter of the cylinder to 0.05 m as a conical bottom having a length of 0.47 m. The spouting air is supplied by a compressed air line is controlled by a gas regulator. The airflow is controlled by a gate valve and a mesh plate having a mesh size less than the size of the bed material is employed as a separator preventing the backflow of the bed material. Images are captured using a high-speed video camera to gain more details of the hydrodynamic characteristics of the flow pattern inside the spouted bed geometry.

Spouted bed

Figure 2: Scheme of a spouted bed (Glatt, Germany).

Experiments & spouted bed results

Experiments are carried out with three different static bed heights of shallow depth wherein the bed height is in the range of factor 2-3 of the Inlet diameter using two different particle distribution classes at 500-710 µm and 700-1000 µm, respectively. Analyzed parameters are the pressure drop across the bed, the bed expansion ratio, and the clusters concerning the superficial gas velocity are focused in the following.

J. Vanamu et al. found that the “bed expansion ratio increases with increasing superficial gas velocity until the onset of external spouting, further increase in the superficial gas velocity, the bed expansion ratio decreases. With increasing the volume of bed, the bed expansion ratio decreases. In a larger volume of bed, the particles tend to spout into the freeboard region rather than expanding with higher superficial gas velocity”. Initial spouting is symmetric, but with increasing superficial gas velocity spouting becomes asymmetric, and asymmetry is more pronounced or starts at lower superficial gas velocities for smaller particles. This agrees with existing theories of hydrodynamic behavior in a fluidized environment. Respecting the necessarity of a proper flow behavior for mixing, coating or drying applications in drug processing, symmetric spouting is essential. In turn, the superficial gas velocity may be kept low.

In case that high superficial gas velocity regimes are required for the operations a draft tube may be installed within the column to achieve the symmetric spout formation.

Summary

This case study highlights the Hydrodynamic behavior of MCC spheres in a spouted bed using image processing method. MCC spheres in the range between 500-710 µm and 700-1000 µm had been employed. All spheres showed a symmetric and asymmetric spouting in the spouted bed. With increasing superficial gas velocity, the fully suspended particles are limited to a certain height in the freeboard region due to the gas-solid crossflow. A change from symmetric to asymmetric spouting is observed with increasing superficial gas velocity.

Keeping the conditions efficient for the mixing, coating or drying applications requires finally to suppress high superficial gas velocities, or changing the setup in such way, that symmetric spouting conditions are kept upright even at higher superficial gas velocities.

References

[1] J. Vanamu and A. Sahoo, Particuology 76 (2023) 101

[2] L. A. P. de Freitas, Particuology 42 (2019) 126

[3] Glatt GmbH, Binzen, Germany. Online on Nov 8, 2022: Spouted bed systems – Glatt – Integrated Process Solutions

Great thanks to Arihant Innochem Pvt. Ltd. who supplied and donated CELLETS® for this study.

Metoprolol pellets

Abstract on Metoprolol pellets

Metoprolol Tartrate is a salt of Metoprolol, a selective β1-receptor blocker medication. The application is the treatment of high blood pressure, chest pain due to poor blood flow to the heart, and several conditions involving an abnormally fast heart rate [2]. In the following, an attempt is shown, wherein MCC spheres are used as starter cores for a multi-layer pellet formulation.

This case study is a short abstract of the publication by P. Wanasawas et al. [1] and presents controlled release Metoprolol Tartrate layered pellets achieving colon-specific drug delivery.

Pellet technology attempt

In the following, in-situ calcium pectinate-coated MCC pellets (CELLETS® 700) were proposed by applying an alternate coating method to drug-layered pellets to achieve colon-specific drug delivery. Using a centrifugal granulator, inert MCC pellets were layered by a Metoprolol Tartrate water-soluble model drug. A protective HPMC layer helps to strengthen cracks or delamination from the core in the later stage of the coating processes. Then, alternate coatings of pectin and calcium chloride layers were spray coated by fluidized bed bottom spray technology (GPCG-1, Glatt®, Germany). This technology allows achieving uniform coating layers. The subcoating with pectin and calcium pectinate polymers allow site-specific drug delivery targeting the colon due to their low water solubility. Both excipients additionally degraded completely by gut microflora [3].

By testing different composition in multilayer coatings with calcium and pectin, some interesting phenomena are stated:

  • the release behavior follows the Higuchi model
  • the drug release can be described by a diffusion control mechanism
  • the coating of the outermost layer defines the success in controlled drug release

The latter point issues the importance of the outermost layer which is whether composed by pectin or calcium. In case of calcium, the drug release was accelerated independently of the number of Ca/P layers, such that a 4-layer system (P/Ca/P/Ca) yield a faster drug release that a 3-alyer system (P/Ca/P), see Figure 1. This is explained by the effect of the calcium ions in the outermost layer, leading to a weakening in the calcium pectinate coating layer.

Metoprolol pellets

Figure 1: Metoprolol pellets. From left to right: Ca/P, P/Ca/P, Ca/P/Ca/P layered pellets. Colors: Cellets as MCC pellet (green), Metoprolol Tartrate (orange), Talcum (blue), Calcium (white), Pectin (grey).

Once, pectin is the component in the outermost layer, this led to a difference in drug release at neutral and slightly acidic conditions of the dissolution media. While in a neutral pH 7.4 buffer, the dissolution kinetics were comparable for a P/Ca/P-system and Ca/P-system, the situation changes in a slightly acidic buffer at pH 6.0. In a phosphate buffer at pH 6.0 the dissolution of a P/Ca/P-system was faster than of a Ca/P-system due to the almost complete ionization of pectin at pH 6.0.

Summary

This case study highlights the controlled release profile of Metoprolol Tartrate as a water-soluble model drug. The formulation is based on CELLETS® 700, which serve as inert MCC spheres. By a variation in the multi-layer composition of calcium and pectin, the dissolution kinetics and controlled release profiles were examined.

Acknowledgement

This research was funded by Thailand Research Fund through Royal Golden Jubilee Ph.D. Program, grant number PHD/00005/2541.

References

[1] P. Wanasawas, A. Mitrevej, N. Sinchaipanid, Pharmaceutics 14 (2022) 1061, https://doi.org/10.3390/pharmaceutics14051061

[2] The American Society of Health-System Pharmacists. Archived from the original on 12 March 2014. Retrieved 21 April 2014. https://web.archive.org/web/20140312062359/http://www.drugs.com/monograph/metoprolol-succinate.html

[3] M. Khotimchenko, Int. J. Biol. Macromol. 158 (2020) 1110-1124. https://doi.org/10.1016/j.ijbiomac.2020.05.002