CELLETS® Technical Resources

CELLETS® are pellets or spheres made of microcrystalline cellulose. The size ranges from 100 µm to 1400 µm. Being neutral starter cores, they can be used as carrier system for low-dosed APIs and allow diverse functional coating. See pellet technologies for a detailed description.

CS_sphericity_image_4

Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.

Available size classes are (click for more information):

Any size class of CELLETS® have same striking advantages:

  • low friability and extreme hardness
  • insolubility in water
  • high spherictity
  • smooth surface
  • good monodispersity

See case studies to see these starter pellets in action!

Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating
, ,

Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating

Abstract on Continuous Manufacturing

Using cocrystals has emerged as a promising strategy to improve the physicochemical properties of active pharmaceutical ingredients (APIs) by forming a new crystalline phase from two or more components. Particle size and morphology control are key quality attributes for cocrystal medicinal products. The needle-shaped morphology is often considered high-risk and complex in the manufacture of solid dosage forms. Cocrystal particle engineering requires advanced methodologies to ensure high-purity cocrystals with improved solubility and bioavailability and with optimal crystal habit for industrial manufacturing. In this study, 3D-printed microfluidic chips were used to control the cocrystal habit and polymorphism of the sulfadimidine (SDM): 4-aminosalicylic acid (4ASA) cocrystal. The addition of PVP in the aqueous phase during mixing resulted in a high-purity cocrystal (with no traces of the individual components), while it also inhibited the growth of needle-shaped crystals. When mixtures were prepared at the macroscale, PVP was not able to control the crystal habit and impurities of individual mixture components remained, indicating that the microfluidic device allowed for a more homogenous and rapid mixing process controlled by the flow rate and the high surface-to-volume ratios of the microchannels. Continuous manufacturing of SDM:4ASA cocrystals coated on beads was successfully implemented when the microfluidic chip was connected in line to a fluidized bed, allowing cocrystal formulation generation by mixing, coating, and drying in a single step.

Conclusions

SDM:4ASA cocrystal particle engineering has been successfully achieved using 3D-printed microfluidic chips. The addition of PVP in the aqueous phase during mixing has allowed the inhibition of needle-shaped crystals and the generation instead of spherical crystal habits with higher purity compared to conventional mixing. A successful continuous manufacturing method for the fabrication of cocrystal-coated particles has been demonstrated by the combination of microfluidic chips with a fluidized bed, allowing the process intensification of mixing and drying in one step.

Authors:

Aytug Kara, Dinesh Kumar, Anne Marie Healy, Aikaterini Lalatsa, and Dolores R. Serrano.

Read more

Read more on continuous manufacturing of cocrystals by Kara et al. here and find out the functionality of CELLETS® 500 (pellets made of microcrystalline cellulose, size: 500-710 µm).
/by
Modelling the disintegration of pharmaceutical tablets
, , ,

Modelling the disintegration of pharmaceutical tablets: integrating a single particle swelling model with the discrete element method

Read more
/by
Development of a New Bioequivalent Omeprazole Productingredientpharm
,

Development of a New Bioequivalent Omeprazole Product

The publication by G. Kumisbek, D. Vetchý, A. Kadyrbay describes gently the development and implementation of a new generic enteric form of CELLETS® 700 (MCC pellets, 700-1000 µm) loaded with omeprazole in capsules by Viva Pharm LLP, a pharmaceutical company based in Kazakhstan. The company’s solid-dosage-form production facility was utilized for this purpose. Detailed technological parameters for production were established and documented in production protocols for commercial batches. Stability testing confirmed the viability of the developed drug in two types of packaging. An analytical normative document containing comprehensive quality control test methods was created for both experimental purposes and the registration dossier.

Equivalence to the innovative drug, Losec®, was demonstrated through dissolution profile testing and Bioequivalence Study (BES). The aim is to commercialize the new generic drug in the pharmaceutical market of Kazakhstan upon obtaining marketing authorization. This initiative aligns with Kazakhstan’s strategy to localize pharmaceutical production, mirroring similar practices in Europe, to ensure affordable and high-quality medicines for its population. The successful development and localization of this generic omeprazole formulation signify a step towards enhancing access to essential medications within Kazakhstan.

Abstract

Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.

Materials

The following materials were used in the study: omeprazole (Hetero Labs, Hyderabad, India) Active Pharmaceutical Ingredient (API), lactose monohydrate Supertab 22AN (Glentnam Life Sciences Ltd., Corsham, UK), sodium lauryl sulfate (RNDr Kulich Pharma s.r.o., Hradec Králové, Czech Republic), disodium hydrogen phosphate dodecahydrate cryst. EMPROVE® (Merck KGaA, Darmstadt, Germany), hydroxypropylmethylcellulose (Tailopur 603), hydroxypropyl cellulose Klucel EF Pharm (Ashland Industries Europe GmbH, Schaffhausen, Switzerland), pellets from microcrystalline cellulose (MCC) Cellets®700 (International Process center GmbH & Co. KG, Dresden, Germany), polyethylene glycol 400 (Applichem GmbH, Darmstadt, Germany), methacrylic acid–ethyl acrylate copolymer Eudragit® L30-D55 (Evonic Nutrition and Care GmbH, Darmstadt, Germany), hard gelatin capsules size 0 (Capsugel, Bornem, Belgium), PlasAcryl® HTP20 (Emerson Resources Ink., Norristown, PA, USA), titanium dioxide (Venator Germany GmbH, Krefeld, Germany), talc (Imerys Talc Italy S.p.A, Porte, Italy). All ingredients were of pharmaceutical production grade as described in the European Pharmacopoeia, and are widely used in preparations for oral use at concentrations not exceeding the recommended limits. Losec®, enteric capsules, 20 mg, AstraZeneca AB, Sweden, was used as the reference drug.

Conclusion

The quantitative and qualitative composition and technology for producing a new generic enteric form of omeprazole in capsules were developed and implemented at the solid-dosage-form production facility of the company Viva Pharm LLP, located in Kazakhstan. The technological parameters of the production process were established and specified in production protocols for commercialized product batches. The developed drug in two types of packaging has passed the stability test. An analytical normative document consisting of full quality control test methods was created for the experimental part and the registration dossier. The equivalence of the generic formulation omeprazole Viva Pharm, enteric capsules, to the innovative drug Losec®, enteric capsules, was proved by the dissolution profile test and BES. The new generic drug is aimed to be commercialized in the pharmaceutical market of the Republic of Kazakhstan after obtaining marketing authorization. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and high-quality medicines.

Source: Medicina 2024, 60(3), 427

/by
Paediatric solid oral dosage forms for combination products: Improving in vitro swallowability of minitablets using binary mixtures with pellets
, ,

Paediatric solid oral dosage forms for combination products: Improving in vitro swallowability of minitablets using binary mixtures with pellets

Abstract on paediatric solid oral dosage forms

There is a growing interest in enhancing the acceptability of paediatric pharmaceutical formulations. Solid oral dosage forms (SODF), especially multiparticulates, are being considered as an alternative to liquid formulations, but they may compromise palatability when large volumes are required for dosing. We hypothesised that a binary mixture of multiparticulates for paediatric use, designed to increase the formulation maximum packing fraction, could reduce the viscosity of the mixture in soft food and facilitate swallowing.

Using the Paediatric Soft Robotic Tongue (PSRT) – an in vitro device inspired by the anatomy and physiology of 2-year-old children – we investigated the oral phase of swallowing for multi-particulate formulations, i.e., pellets (350 and 700 µm particles), minitablets (MTs, 1.8 mm), and their binary mixtures (BM), by evaluating oral swallowing time, the percentage of particles swallowed, and post-swallow residues. We also conducted a systematic analysis of the effect of the administration method, bolus volume, carrier type, particle size, and particle volume fraction on pellets swallowability.

The results demonstrated that the introduction of pellets affected the flowing ability of the carriers, increasing shear viscosity. The size of the pellets did not appear to influence particle swallowability but raising the particle volume fraction (v.f.) above 10% resulted in a decrease in the percentage of particles swallowed. At v.f. 0.4, pellets were easier to swallow (+ 13.1%) than MTs, being the administration method used highly dependent on the characteristics of the multi-particulate formulation under consideration. Finally, mixing MTs with only 24% of pellets improved particle swallowability, achieving swallowing levels similar to those of pellets alone. Thus, combining SODF, i.e., MTs and pellets, improves MT swallowability, and offers new possibilities for adjusting product palatability, being particularly attractive for combination products.

Authors: Alejandro Avila-Sierra, Anais Lavoisier, Carsten Timpe, Peter Kuehl, Leonie Wagner, Carole Tournier, Marco Ramaioli

Read more

Get the full publication on paediatric solid oral dosage forms by Alejandro Avila-Sierra et al. here. Used MCC pellet: Cellets 350 and Cellets 700.

/by
Comparison of Mini-Tablets and Pellets as Multiparticulate Drug Delivery Systems for Controlled Drug Release
,

Comparison of Mini-Tablets and Pellets as Multiparticulate Drug Delivery Systems for Controlled Drug Release

Multiparticulate Drug Delivery Systems: Advantages and Applications

Multiparticulate drug delivery systems offer clear advantages for controlled drug release. Manufacturers can place mini-tablets in hard capsules or administer them using special dosing units. Similarly, they can give pellets in hard capsules or compress them into tablets. Together, these forms provide flexible and precise drug delivery with polymer coatings.

In this study [1], researchers prepared four solid drug formulations and analyzed their drug release. First, they coated inert pellets with the model drug sodium benzoate. Next, they added a layer of insoluble ethyl cellulose. Afterward, they compressed the coated pellets into mini-tablets and normal tablets. Meanwhile, they directly compressed another type of mini-tablet from a sodium benzoate mixture and coated it with ethyl cellulose. They applied the coating using fluidized bed technology.

The coated pellets showed a lag time and retarded release. Afterward, the release followed first-order kinetics. In contrast, mini-tablets and normal tablets made from coated pellets released sodium benzoate without a lag time. This occurred because tableting partially disrupted the ethyl cellulose layer. Moreover, directly compressed mini-tablets released sodium benzoate more slowly as the coating thickness increased.

Therefore, the different formulations of coated pellets, mini-tablets, and normal tablets provide a wide range of drug release profiles. Consequently, they can meet various biopharmaceutical and pharmacological requirements.

Ethyl Cellulose-coated Mini-Tablets as Multiparticulate Drug Delivery Systems

Multiparticulate drug delivery systems can be made by compressing drug- and polymer-coated pellets into mini-tablets or normal tablets. Moreover, pellets and mini-tablets compressed into tablets spread widely in the small intestine. This improves drug absorption and increases bioavailability compared to normal tablets. In both tablet types, the sodium benzoate release slows down depending on the thickness and properties of the ethylcellulose coating.

Additionally, ethylcellulose-coated mini-tablets made by directly compressing sodium benzoate with excipients provide an alternative multiparticulate drug delivery method. These mini-tablets release the drug slowly, and the rate depends on the coating thickness. Consequently, they are suitable for prolonged-release applications. Furthermore, their release variation is higher than that of pellets or normal multiple-unit tablets made from pellets.

Finally, sodium benzoate layering on pellets using a fluidized bed, followed by tableting, works for both mini-tablets and normal tablets. Therefore, manufacturers can adjust the final pharmaceutical form to create diverse release profiles, which can support marketing or patenting strategies.

Read more

Read more about how CELLETS 200 are employed in mini-tablets and pellets as multiparticulate drug delivery systems by F. Priese et al.

Authors

F. Priese, D. Wiegel, C. Funaro, G. Mondelli, and B. Wolf, Coatings 2023, 13(11), 1891; doi:10.3390/coatings13111891
/by

Investigating the Influence of Fluid-Bed Equipment Design and Size on Particle Coating Thickness Trends and Drug Prolonged-Release Profiles Linked to Particle Size

The primary objective of this research is to investigate the design and size on particle coating thickness. Furthermore,  illustrate how the design, size, and configurations of fluid-bed coating machinery influence variations in pellet coating thickness. This parameter plays a crucial role in governing the release of medication in prolonged-release pellets. Initially, the scientists conducted a series of coating experiments where the pellet cores were coated with Tartrazine dye. The aim was to evaluate the performance of the coating equipment in terms of the distribution of coating thickness, which was assessed based on color hue.

In the subsequent set of experiments, drug-layered pellets underwent film-coating with prolonged-release material. Brezovar et al. conducted dissolution profile tests to gauge the uniformity and thickness of the coating among pellets of different sizes. Pellets of kind CELLETS® 700 (IPC Dresden, Germany) had been employed. This investigation encompassed both laboratory and pilot scale applications. Laboratory-sized fluid-bed coaters GPCG1 (Glatt GmbH, Germany and BX FBD10, Brinox d.o.o., Slovenia) and a pilot-sized (BX FBD30, Brinox d.o.o., Slovenia) fluid-bed coater are used for these tests. The group made comparisons between two types of distribution plates and various adjustments in the height of the draft tube.

The dye coating study yielded highly valuable insights. The results provided the basis for refining the process and optimizing the utilization of process equipment, especially in conjunction with the appropriate process parameters. On the laboratory scale, we observed a preference for film coating larger drug-containing pellets. However, on the pilot scale, we achieved a preferential coating of smaller pellets through judicious adjustments, a development that holds significance in achieving a drug release profile independent of particle size for prolonged-release dosage forms.

Link to publication:

The Effect of Design and Size of the Fluid‑Bed Equipment on the Particle Size‑Dependent Trend of Particle Coating Thickness and Drug Prolonged‑Release Profile
AAPS PharmSciTech (2023) 24, 93. doi:10.1208/s12249-023-02540-9
T. Brezovar, G. Hudovornik, M. Perpar, M. Luštrik, R. Dreu

/by
Critical aspects of starter spheres in oral pellet formulations one should consideringredientpharm
, , , , , ,

Critical aspects of starter spheres in oral pellet formulations one should consider

Read more
/by
Preparation and characterization of controlled-release doxazosin mesylate pelletsingredientpharm

Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique

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.

Need formulation services?

Contact our partner Glatt Pharmaceutical Services!

/by
Pore Former basic drugs

Design and Optimization of a Nanoparticulate Pore Former as a Multifunctional Coating Excipient for pH Transition-Independent Controlled Release of Weakly Basic Drugs for Oral Drug Delivery

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.
Pharmaceutics 15 00547 g001 550
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

  1. Dvořáčková, K.; Doležel, P.; Mašková, E.; Muselík, J.; Kejdušová, M.; Vetchý, D. The effect of acid pH modifiers on the release characteristics of weakly basic drug from hydrophlilic-lipophilic matrices. AAPS Pharmscitech 2013, 14, 1341–1348. [Google Scholar] [CrossRef] [PubMed]
  2. Bassi, P.; Kaur, G. pH modulation: A mechanism to obtain pH-independent drug release. Expert Opin. Drug Deliv. 2010, 7, 845–857. [Google Scholar] [CrossRef]
  3. Sun, Y.; Koyama, Y.; Shimada, S. Measurement of intraluminal pH changes in the gastrointestinal tract of mice with gastrointestinal diseases. Biochem. Biophys. Res. Commun. 2022, 620, 129–134. [Google Scholar] [CrossRef] [PubMed]
  4. Vinarov, Z.; Abdallah, M.; Agundez, J.A.G.; Allegaert, K.; Basit, A.W.; Braeckmans, M.; Ceulemans, J.; Corsetti, M.; Griffin, B.T.; Grimm, M.; et al. Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. Eur. J. Pharm. Sci. 2021, 162, 105812. [Google Scholar] [CrossRef] [PubMed]
  5. Thoma, K.; Ziegler, I. The pH-independent release of fenoldopam from pellets with insoluble film coats. Eur. J. Pharm. Biopharm. 1998, 46, 105–113. [Google Scholar] [CrossRef]
  6. Bolourchian, N.; Dadashzadeh, S. PH-independent release of propranolol hydrochloride from HPMC-based matrices using organic acids. Daru 2008, 16, 136–142. [Google Scholar]
  7. Nie, S.; Pan, W.; Li, X.; Wu, X. The effect of citric acid added to hydroxypropyl methylcellulose (HPMC) matrix tablets on the release profile of vinpocetine. Drug Dev. Ind. Pharm. 2004, 30, 627–635. [Google Scholar] [CrossRef] [PubMed]
  8. Espinoza, R.; Hong, E.; Villafuerte, L. Influence of admixed citric acid on the release profile of pelanserin hydrochloride from HPMC matrix tablets. Int. J. Pharm. 2000, 201, 165–173. [Google Scholar] [CrossRef]
  9. Streubel, A.; Siepmann, J.; Dashevsky, A.; Bodmeier, R. pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets. J. Control. Release 2000, 67, 101–110. [Google Scholar] [CrossRef] [PubMed]
  10. Obaidat, A. Modulation of the micro-environmental pH and its influence on the gel layer behavior and release of theophylline from hydrophilic matrices. Int. J. Pharma. Bio Sci. 2013, 4, P794–P802. [Google Scholar]
  11. Siepe, S.; Lueckel, B.; Kramer, A.; Ries, A.; Gurny, R. Assessment of tailor-made HPMC-based matrix minitablets comprising a weakly basic drug compound. Drug Dev. Ind. Pharm. 2008, 34, 46–52. [Google Scholar] [CrossRef] [PubMed]
  12. Siepe, S.; Lueckel, B.; Kramer, A.; Ries, A.; Gurny, R. Strategies for the design of hydrophilic matrix tablets with controlled microenvironmental pH. Int. J. Pharm. 2006, 316, 14–20. [Google Scholar] [CrossRef] [PubMed]
  13. Akiyama, Y.; Yoshioka, M.; Horibe, H.; Hirai, S.; Kitamori, N.; Toguchi, H. pH-independent controlled-release microspheres using polyglycerol esters of fatty acids. J. Pharm. Sci. 1994, 83, 1600–1607. [Google Scholar] [CrossRef]
  14. Lecomte, F.; Siepmann, J.; Walther, M.; MacRae, R.J.; Bodmeier, R. Blends of enteric and GIT-insoluble polymers used for film coating: Physicochemical characterization and drug release patterns. J. Control. Release 2003, 89, 457–471. [Google Scholar] [CrossRef]
  15. Sakellariou, P.; Rowe, R.C.; White, E.F.T. Polymer/polymer interaction in blends of ethyl cellulose with both cellulose derivatives and polyethylene glycol 6000. Int. J. Pharm. 1986, 34, 93–103. [Google Scholar] [CrossRef]
  16. Sakellariou, P.; Rowe, R.C. Phase separation and morphology in ethylcellulose/cellulose acetate phthalate blends. J. Appl. Polym. Sci. 1991, 43, 845–855. [Google Scholar] [CrossRef]
  17. Lecomte, F.; Siepmann, J.; Walther, M.; MacRae, R.J.; Bodmeier, R. pH-Sensitive polymer blends used as coating materials to control drug release from spherical beads: Elucidation of the underlying mass transport mechanisms. Pharm. Res. 2005, 22, 1129–1141. [Google Scholar] [CrossRef]
  18. Khan, M.Z.; Prebeg, Z.; Kurjaković, N. A pH-dependent colon targeted oral drug delivery system using methacrylic acid copolymers. I. Manipulation Of drug release using Eudragit L100-55 and Eudragit S100 combinations. J. Control. Release 1999, 58, 215–222. [Google Scholar] [CrossRef]
  19. John, R.; Howard, P.T. Controlled Release Formulation. U.S. Patent US4792452A, 20 December 1988. [Google Scholar]
  20. Amighi, K.; Timmermans, J.; Puigdevall, J.; Baltes, E.; Moës, A.J. Peroral sustained-release film-coated pellets as a means to overcome physicochemical and biological drug-related problems. I. In vitro development and evaluation. Drug Dev. Ind. Pharm. 1998, 24, 509–515. [Google Scholar] [CrossRef]
  21. Gruber, P.; Brickl, R.; Bozler, G.; Stricker, H. Dipyricamole Sustained Release Forms Comprising Lacquer-Coated Particles and the Preparation Thereof. U.S. Patent US4367217A, 4 January 1983. [Google Scholar]
  22. Cole, E.T.; Scott, R.A.; Connor, A.L.; Wilding, I.R.; Petereit, H.U.; Schminke, C.; Beckert, T.; Cadé, D. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int. J. Pharm. 2002, 231, 83–95. [Google Scholar] [CrossRef]
  23. Felton, L.A.; Porter, S.C. An update on pharmaceutical film coating for drug delivery. Expert Opin. Drug. Deliv. 2013, 10, 421–435. [Google Scholar] [CrossRef] [PubMed]
  24. Frohoff-Hülsmann, M.A.; Lippold, B.C.; McGinity, J.W. Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl-cellulose as coating material for diffusion pellets II: Properties of sprayed films. Eur. J. Pharm. Biopharm. 1999, 48, 67–75. [Google Scholar] [CrossRef] [PubMed]
  25. Jacob, J.; Haponiuk, J.T.; Thomas, S.; Gopi, S. Biopolymer based nanomaterials in drug delivery systems: A review. Mater. Today Chem. 2018, 9, 43–55. [Google Scholar] [CrossRef]
  26. Luliński, P. Molecularly imprinted polymers based drug delivery devices: A way to application in modern pharmacotherapy. A review. Mater. Sci. Eng. C 2017, 76, 1344–1353. [Google Scholar] [CrossRef] [PubMed]
  27. Shamsi, M.; Mohammadi, A.; Manshadi, M.K.D.; Sanati-Nezhad, A. Mathematical and computational modeling of nano-engineered drug delivery systems. J. Control. Release 2019, 307, 150–165. [Google Scholar] [CrossRef]
  28. Al Ragib, A.; Chakma, R.; Dewan, K.; Islam, T.; Kormoker, T.; Idris, A.M. Current advanced drug delivery systems: Challenges and potentialities. J. Drug Deliv. Sci. Technol. 2022, 76, 103727. [Google Scholar] [CrossRef]
  29. Davoodi, P.; Lee, L.Y.; Xu, Q.; Sunil, V.; Sun, Y.; Soh, S.; Wang, C.-H. Drug delivery systems for programmed and on-demand release. Adv. Drug Deliv. Rev. 2018, 132, 104–138. [Google Scholar] [CrossRef] [PubMed]
  30. Liu, Z.; Cheung, R.; Wu, X.Y.; Ballinger, J.R.; Bendayan, R.; Rauth, A.M. A study of doxorubicin loading onto and release from sulfopropyl dextran ion-exchange microspheres. J. Control. Release 2001, 77, 213–224. [Google Scholar] [CrossRef]
  31. Wong, H.L.; Bendayan, R.; Rauth, A.M.; Wu, X.Y. Development of solid lipid nanoparticles containing ionically complexed chemotherapeutic drugs and chemosensitizers. J. Pharm. Sci. 2004, 93, 1993–2008. [Google Scholar] [CrossRef]
  32. Shalviri, A.; Raval, G.; Prasad, P.; Chan, C.; Liu, Q.; Heerklotz, H.; Rauth, A.M.; Wu, X.Y. pH-Dependent doxorubicin release from terpolymer of starch, polymethacrylic acid and polysorbate 80 nanoparticles for overcoming multi-drug resistance in human breast cancer cells. Eur. J. Pharm. Biopharm. 2012, 82, 587–597. [Google Scholar] [CrossRef]
  33. Shalviri, A.; Chan, H.K.; Raval, G.; Abdekhodaie, M.J.; Liu, Q.; Heerklotz, H.; Wu, X.Y. Design of pH-responsive nanoparticles of terpolymer of poly(methacrylic acid), polysorbate 80 and starch for delivery of doxorubicin. Colloids Surf. B Biointerfaces 2013, 101, 405–413. [Google Scholar] [CrossRef] [PubMed]
  34. Chen, K.; Chang, H.H.R.; Shalviri, A.; Li, J.; Lugtu-Pe, J.A.; Kane, A.; Wu, X.Y. Investigation of a new pH-responsive nanoparticulate pore former for controlled release enteric coating with improved processability and stability. Eur. J. Pharm. Biopharm. 2017, 120, 116–125. [Google Scholar] [CrossRef] [PubMed]
  35. Yoshida, M.I.; Gomes, E.C.L.; Soares, C.D.V.; Cunha, A.F.; Oliveira, M.A. Thermal Analysis Applied to Verapamil Hydrochloride Characterization in Pharmaceutical Formulations. Molecules 2010, 15, 2439–2452. [Google Scholar] [CrossRef] [PubMed]
/by
Amorphous Solid Dispersions Layered onto Pellets - An Alternative to Spray Drying

Amorphous Solid Dispersions Layered onto Pellets – An Alternative to Spray Drying?

This article “Amorphous Solid Dispersions Layered onto Pellets – An Alternative to Spray Drying?” is an excerpt from the publication of Neuwirth et al., Pharmaceutics 2023, 15(3), 764; https://doi.org/10.3390/pharmaceutics15030764.

Abstract

Spray drying is one of the most frequently used solvent-based processes for manufacturing amorphous solid dispersions (ASDs). However, the resulting fine powders usually require further downstream processing when intended for solid oral dosage forms. In this study, we compare properties and performance of spray-dried ASDs with ASDs coated onto neutral starter pellets in mini-scale. We successfully prepared binary ASDs with a drug load of 20% Ketoconazole (KCZ) or Loratadine (LRD) as weakly basic model drugs and hydroxypropyl-methyl-cellulose acetate succinate or methacrylic acid ethacrylate copolymer as pH-dependent soluble polymers. All KCZ/ and LRD/polymer mixtures formed single-phased ASDs, as indicated by differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy. All ASDs showed physical stability for 6 months at 25 °C/65% rH and 40 °C/0% rH. Normalized to their initial surface area available to the dissolution medium, all ASDs showed a linear relationship of surface area and solubility enhancement, both in terms of supersaturation of solubility and initial dissolution rate, regardless of the manufacturing process. With similar performance and stability, processing of ASD pellets showed the advantages of a superior yield (>98%), ready to use for subsequent processing into multiple unit pellet systems. Therefore, ASD-layered pellets are an attractive alternative in ASD-formulation, especially in early formulation development at limited availability of drug substance.

Materials

The model drugs ketoconazole (KCZ) and loratadine (LRD) were purchased from Sris Pharmaceuticals (Hyderabad, India). HPMCAS LG (hydroxypropyl-methylcellulose acetate succinate, wt%: methoxyl 20–24%, hydroxypropyl 5–9%, succinyl 14–18%; Mw = 18,000, HPMC-AS) was donated from Shin-Etsu Chemical (Tokyo, Japan). Eudragit L100-55 (methacrylic acid ethylacrylate copolymer, ratio 1:1, Mw = 320,000, EL100-55) was donated by Evonik (Darmstadt, Germany). Cellets 1000 (microcrystalline cellulose starter pellets, 1000–1400 µm) were provided by Glatt Pharmaceutical Services (Binzen, Germany). A detailed list of the pellets’ characteristics is shown in Table 1. Ethanol 96% (v/v) (technical grade) used in the sample preparation, and methanol (analytical grade) used for the HPLC analytics as well as the buffer salts disodium mono-hydrogen phosphate dodecahydrate (Na2HPO4·12H2O) and monosodium dihydrogen phosphate dodecahydrate (NaH2PO4·12H2O) were obtained from VWR Chemicals GmbH (Darmstadt, Germany).
Pellet Properties
d50 (xc min) [µm] 1123.44
(±7.36)
SPAN 0.166
(±0.002)
b/l 0.893
(±0.000)
SPHT 0.956
(±0.001)
Particle density [g/cm3] 1.452
(±0.016)
Sm [cm2/g] 36.41
(±0.29)

Table 1. Pellet properties of Cellets 1000. d50: mean particle diameter determined by the particle width; SPAN: width of the particle distribution; b/l: aspect ratio; SPHT: sphericity; Sm: specific surface area.

Pellet Coating (PC)
For pellet coating (PC) a laboratory scale fluid bed system Mini Glatt equipped with a Micro-Kit (Glatt GmbH, Binzen, Germany) was used. The coating was applied with a 0.5 mm two-fluid nozzle in bottom spray using the special bottom plate of the Micro-Kit to emulate a three-fluid nozzle with micro-climate. In the beginning, the machine was filled with 25.0 g of Cellets® 1000. The following process parameters were maintained throughout the process: Process gas flow 30 m3/h, product temperature 30.0 ± 1.0 °C (resulting inlet temperature 32–35 °C), spray pressure 1.5 bar and spray rate 1.0 ± 0.2 g/min. The final pellets had a theoretical drug-load of 10% (w/w) due to the fact that ASD and core pellets were used in a 1:1-ratio. […] To prepare the spraying solutions, the API and polymer were dissolved in ethanol 96% (v/v) under continuous stirring (solid content of 10% (w/w)). Prior to spraying, each solution was sonicated for 15 min to ensure complete dissolution of the components.
Subsequently, the coated pellets were manually sieved with a 2 mm mesh to eliminate multicore pellets. The pellets were dried under vacuum for 24 h at the same conditions as the SD powder.

Conclusions

In this study, we successfully prepared binary single phase ASDs of KCZ and LRD as weakly basic, slow crystallizing model APIs (drug load 20% (w/w)) using HPMC-AS or EL100-55 as pH-dependent soluble polymers via fluid bed pellet coating and spray drying. While the received ASD-pellets would not require further downstream processing other than capsule filling or tableting, the fine SD powder had to be transformed into dry granules. In combination with the slow crystallizers, KTZ and LOR, both manufacturing processes resulted in single-phased ASDs of high physical stability (up to 6 months) and similar dissolution performance when normalized to the total outer surface. The dissolution rate depends mainly on this total outer particle surface of the respective sample, independent of the manufacturing process, while the porosity of the sample had a minor impact on its dissolution behavior.
Especially for early formulation development, the high yield and ease of handling due to the pellet properties are strong advantages over the standard spray drying process. Nevertheless, the long process time in larger scale requires further process optimization in fluidized bed processing.
Amorphous solid dispersions Cellets 20230302

Figure: Amorphous solid dispersions.

[1] Neuwirth et al., Pharmaceutics 2023, 15(3), 764; https://doi.org/10.3390/pharmaceutics15030764

/by