The patent application US20240350420A1 focuses on pharmaceutical formulations and methods for treating conditions such as hyperhidrosis, which involves excessive sweating. The document details the development of modified-release compositions, specifically utilizing Pilocarpine HCl, a muscarinic agonist. These formulations aim to optimize drug delivery by employing various release mechanisms, including immediate, delayed, or sustained release. The innovations include encapsulation techniques using polymer coatings to control dissolution rates under different conditions, ensuring stable and effective drug delivery over time.
Additionally, the application highlights formulations combining Pilocarpine with other agents like Oxybutynin to enhance therapeutic efficacy. The study of dissolution profiles under varying environmental conditions further underscores the emphasis on stability and performance consistency. This approach is designed to improve patient outcomes by tailoring release profiles to meet specific medical needs while minimizing side effects through controlled drug exposure.
Why CELLETS® are important in these methods for treating hyperhidrosis
CELLETS® are microcrystalline cellulose spheres, serving as an essential component in drug delivery systems designed for controlled and extended release of active pharmaceutical ingredients (API). These spheres act as inert core substrates, providing a uniform and stable base for layering the active compounds and functional polymers. Their consistent size and smooth surface allow precise and even distribution of coatings, which is critical for achieving predictable drug release kinetics.
Cellets are the crucial base for formulations relying on pellet technologies. These powerful formulations for oral drug uptake allow improving the pharmacokinetic profile of APIs, especially highly lipophilic drugs, by controlling their release rate. By coating excipients and API, multi-layer systems created on these cores allow gradual drug dissolution, reducing fluctuations in drug plasma levels and minimizing side effects. For example, in this patent of a Pilocarpine HCl formulation, coating CELLETS® with siutable excipients enable extended drug release, maintaining therapeutic concentrations for longer durations and improving patient compliance by reducing dosing frequency.
Their flexibility in application allows them to be used across various dosage forms, such as capsules or compressed tablets and even gel-like dosage forms. Additionally, the uniformity of these MCC starter beads ensures that each pellet provides a controlled dose of the active ingredient, making them integral to achieving consistent therapeutic outcomes in complex drug delivery systems.
The function of Pilocarpine HCl
Pilocarpine HCl is a cholinergic agonist that stimulates muscarinic receptors to increase secretion production and smooth muscle contraction. It is primarily used in ophthalmology to treat glaucoma by reducing intraocular pressure through enhanced aqueous humor outflow. Additionally, it is used in managing xerostomia (dry mouth) caused by conditions like Sjögren’s syndrome or following radiation therapy for head and neck cancers. Its parasympathomimetic action helps stimulate saliva production and improve symptoms.
Document information
Document Type and Number: (“Pharmaceutical compositions and methods for treating hyperhidrosis”).
Kind Code: A1
Inventors:
Stephen Wayne Andrews, Samuel Bruce Balik, John Edward Jett, Robert Michael LEMING
Disclaimer
This text was partly generated by chatGPT engine version GPT‑4o, on Nov 21, 2024. Image was generated with Adobe Firefly.
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Please, find scientific literature on CELLETS®, MCC spheres. This list is constantly updated and does not claim to be complete. If you are author, scientist or R&D specialist, please submit your present publication to us for improving the visibility.
Research article Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating European Journal of Pharmaceutics and Biopharmaceutics, Volume 124, March 2018, Pages 13-27
Dolores R. Serrano, David Walsh, Peter O’Connell, Naila A. Mugheirbi, Zelalem Ayenew Worku, Francisco Bolas-Fernandez, Carolina Galiana, Maria Auxiliadora Dea-Ayuela, Anne Marie Healy
Conference abstract Multiple-unit orodispersible mini-tablets International Journal of Pharmaceutics, Volume 511, Issue 2, 25 September 2016, Page 1128
Anna Kira Adam, Christian Zimmer, Stefan Rauscher, Jörg Breitkreutz
Research article Asymmetric distribution in twin screw granulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 106, September 2016, Pages 50-58
Tim Chan Seem, Neil A. Rowson, Ian Gabbott, Marcelde Matas, Gavin K. Reynolds, AndyIngram
Research article Physical properties of pharmaceutical pellets Chemical Engineering Science, Volume 86, 4 February 2013, Pages 50-60
Rok Šibanc, Teja Kitak, Biljana Govedarica, StankoSrčič Rok Dreu
Research article Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices Chemical Engineering Journal, Volume 164, Issues 2–3, 1 November 2010, Pages 268-274
Jari T. T. Leskinen, Matti-Antero H. Okkonen, Maunu M. Toiviainen, Sami Poutiainen, Mari Tenhunen, Pekka Teppola, Reijo Lappalainen, Jarkko Ketolainen, Kristiina Järvinen
Research article Granule size distribution of tablets Journal of Pharmaceutical Sciences, Volume 99, Issue 4, April 2010, Pages 2061-2069
Satu Virtanen, Osmo Antikainen, Heikki Räikkönen, Jouko Yliruusi
Research article New insights into segregation during tabletting International Journal of Pharmaceutics, Volume 397, Issues 1–2, 15 September 2010, Pages 19-26
S. Lakio, S. Siiriä, H. Räikkönen, S. Airaksinen, T. Närvänen, O. Antikainen, J.Yliruusi
Research article In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 73, Issue 2, October 2009, Pages 280-284
Nele Poelvoorde, Hans Verstraelen, Rita Verhelst, Bart Saerens, Ellen De Backer, Guido Lopes dos Santos Santiago, Chris Vervaet, Mario Vaneechoutte, Fabienne De Boeck, Luc Van Borteld, Marleen Temmerman, Jean-Paul Remon
List – Publications with MCC spheres, 2008 and earlier
Research article Attrition strength of different coated agglomerates Chemical Engineering Science, Volume 63, Issue 5, March 2008, Pages 1361-1369
B. van Laarhoven, S.C.A. Wiers, S.H. Schaafsma, G.M.H. Meesters
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This article “In vitro validation of colon delivery of vitamin B2 through a food grade multi-unit particle system” discusses a novel method for delivering active ingredients, particularly riboflavin, to the colon in a food-grade, environmentally friendly form using a double-layer coated multi-unit particle system (MUPS). The MUPS uses a shellac outer layer, alginate inner layer, and cellulose core, maintaining integrity through upper digestive processes. Tests showed it releases about 90% of riboflavin in the colon, enhancing gut health by promoting beneficial short-chain fatty acids. This sustainable approach addresses rising demand for effective colon-targeted health products and aligns with EU regulations limiting microplastic use in consumable goods.
The MUPS containing riboflavin, branded as Humiome® B2 by DSM-Firmenich, utilizes cellulose pellets known as CELLETS® as the core material. The manufacturing process involves a fluid bed layering method, where riboflavin and pectin are applied as a binder onto the Cellets. The MUPS is then coated with layers of sodium alginate and hardened with calcium chloride, followed by a shellac outer layer. This design ensures a controlled, colonic release, offering an efficient, food-grade delivery system for active nutrients.
The study demonstrates the efficacy of a shellac-alginate MUPS for targeted delivery of riboflavin to the colon, using food-grade materials that align with environmental standards. In vitro models validated its effectiveness, with around 90% of riboflavin reaching the colonic region. Results show promise for health benefits linked to microbiome modulation and short-chain fatty acid production. Future clinical studies will focus on the impact of this delivery system on microbiome and host health, supporting its potential in functional foods, supplements, and medical nutrition.
Abstract
Colon target delivery of active ingredients is frequently applied in pharmaceutical products. However, in functional food and beverage applications, dietary supplements, and medical nutrition, formats targeting colonic delivery to improve human health are rare. Nevertheless, there is emerging evidence for beneficial effects of colonic delivered nutrients on gut microbiota and host health which increases the demand for sustainable food grade materials that are regulatory approved for application. In this paper, we describe a double layer coated multi-unit particle system (MUPS) with a diameter of approximately 730 microns consisting of food grade materials: shellac as outer layer, alginate as inner layer, cellulose as a core and riboflavin as active ingredient. The suitability of the MUPS for colonic delivery was tested in three well-established in vitro digestion and fermentation models: the USP Apparatus 3 and the TNO Intestinal Models 1 and 2 (TIM-1 and TIM-2). All systems confirmed the integrity of the MUPS under simulated upper gastrointestinal tract conditions with approximately 90% of the active ingredient being released under simulated ileal-colonic conditions. The TIM-2 model also showed the effects of riboflavin loaded MUPS on the microbiome composition with an increase in the production of short-chain fatty acids, acetate and butyrate. The results of these experiments provide a reliable basis for validation of this vitamin-loaded food grade MUPS in future human clinical trials. In addition, following the recent announcement of the European Commission to restrict intentionally added microplastics to products, the materials used in the described formulation offer an environmentally friendly alternative to often applied methyl acrylate based coatings.
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The patent application US20240139215A1 focuses on the development of controlled release formulations for highly lipophilic physiologically active substances, such as cannabinoids. These substances tend to have high lipid solubility (log P of 4 or more), making them difficult to deliver in a controlled and effective manner. This patent addresses the need for efficient controlled release systems that can provide consistent therapeutic effects by utilizing a matrix-based approach.
The formulation includes a matrix that contains one or more highly lipophilic active substances and water-soluble binders like hydroxypropyl methyl cellulose (HPMC), methyl cellulose (MC), or similar polymers. The key challenge with such substances is their tendency to release slowly and incompletely when taken orally, which this patent solves by adjusting the proportion of water-soluble binders. The binder content is carefully selected to be between 0.1-10% of the total matrix weight, optimizing the release rate of the active substances over the gastrointestinal transit time.
One of the innovative aspects of the invention is the use of matrix pellets, which are small particles with a size range of 30 µm to 1800 µm. These pellets may be administered in various forms, such as capsules, tablets, or sachets. The flexibility of the dosage forms makes it easier to control and adjust the release kinetics of the active ingredients.
The CELLETS® play a crucial role in this formulation. They are used as neutral cores for the deposition of the active substances and their binders. CELLETS® are microcrystalline cellulose spheres that provide an ideal substrate for layering the active substance and polymers, ensuring uniform distribution and controlled release. By using these CELLETS®, the formulation can achieve a more predictable and consistent release profile, crucial for substances like cannabinoids that require precise dosing to avoid psychoactive side effects while maintaining therapeutic efficacy.
Additionally, these pellets can be coated with other materials to further control the release rate if desired, though this is optional. In many embodiments, the matrix pellets themselves are sufficient to achieve the desired controlled release without the need for additional coatings.
In conclusion, the US20240139215A1 patent introduces a novel approach to the controlled release of highly lipophilic substances, leveraging matrix technology with carefully chosen water-soluble binders and neutral cores like CELLETS®. This method ensures effective delivery and consistent release, addressing the challenges posed by the lipophilic nature of substances like cannabinoids. In this specific patent, the following MCC Sphere types are recommended: CELLETS® 500.
Document information
Document Type and Number: (“Controlled release formulations of highly lipophilic physiologically active substances”)
Kind Code: A1
Inventors:
Mirko Nowak
Jay Jesko Nowak
Annette Grave
Monika Wentzlaff
Sarah Barthold
Christian Geugelin
Disclaimer
This text was generated by chatGPT engine version GPT‑4o, on Oct 21, 2024. Image was generated with Adobe Firefly.
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Compaction pressure can induce an undesirable solid-state polymorphic transition in drugs, fragmentation, loss of coated pellet integrity, and the decreased viability and vitality of microorganisms. Thus, the excipients with increased plasticity can be considered as an option to decrease the undesirable effects of compaction pressure. This study aims to increase the plasticity (to reduce the mean yield pressure; Py) of dried microcrystalline cellulose (MCC) by loading it with a specially selected plasticizer. Diethyl citrate (DEC), water, and glycerol were the considered plasticizers. Computation of solubility parameters was used to predict the miscibility of MCC with plasticizers (possible plasticization effect). Plasticizer-loaded MCC spheres with 5.0 wt.% of water, 5.2 wt.% of DEC, and 4.2 wt.% glycerol were obtained via the solvent method, followed by solvent evaporation. Plasticizer-loaded formulations were characterised by TGA, DSC, pXRD, FTIR, pressure-displacement profiles, and in-die Heckel plots. Py was derived from the in-die Heckel analysis and was used as a plasticity parameter. In comparison with non-plasticized MCC (Py = 136.5 MPa), the plasticity of plasticizer-loaded formulations increased (and Py decreased) from DEC (124.7 MPa) to water (106.6 MPa) and glycerol (99.9 MPa), and that was in full accordance with the predicted miscibility likeliness order based on solubility parameters. Therefore, water and glycerol were able to decrease the Py of non-plasticized MCC spheres by 16.3 and 30.0%, respectively. This feasibility study showed the possibility of modifying the plasticity of MCC by loading it with a specially selected plasticizer.
References to “The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer”
Authors: Artūrs Paulausks, Tetiana Kolisnyk and Valentyn Mohylyuk
Being non-invasive and, in most cases, not requiring medical assistance, tablets for oral administration are the most widespread and the most popular pharmaceutical and nutraceutical dosage forms. Despite the rising topic of individualised/personalised medicine, including individualised dosing, drug release, and customer properties, national healthcare systems worldwide are highly dependent on the mass-market production of tablets and their usage following treatment protocols.
In the vast majority of cases, pharmaceutical substances cannot be converted into tablets via tableting with high-speed rotary tablet presses [1]. To achieve the desirable mechanical and biopharmaceutical properties, specific excipients are required. Appropriate mechanical properties, such as tablet hardness (or tensile strength) and abrasion resistance (friability) should ensure tablet applicability to transportation, coating, and packaging processes without losing their appearance, dose, and biopharmaceutical properties. Moreover, the intrinsic properties of tablet excipients and the structural-mechanical properties of the tablets formed eventually affect the disintegration and drug release behaviour of the dosage form, and so, can be deliberately selected to achieve the desired release profile [2].
Upon tableting, the compaction pressure and tableting speed (dwell time) induce elastic and plastic deformation, or fragmentation, and affect the extent of these deformations [3]. The tableting cycle can be described with a force–displacement profile: the distance between punches, which is plotted against the compaction pressure or force. This can be determined with state-of-the-art equipment, such as compaction simulators containing hi-tech sensors and sophisticated user-friendly software [4,5].
Figure 1. An example of a force-displacement profile highlighting: the rearrangement energy (E1), plastic energy (E2 + E4), elastic energy (E3; or energy lost), plastic flow energy (E4), compaction energy (E1 + E2 + E3), and mean yield pressure (Py). The arrows on the curve are showing the direction of curve development.
Considering the true density of the material, an in-die Heckel plot can be built: ln(1/porosity) is plotted against the compaction pressure. The greater the slope of the linear region (K), the greater the degree of plasticity of the material [6]. The mean yield pressure (Py) of the solid is reciprocal to K [7] and describes the point after which the deformation is irreversible (pointed out in Figure 1). It should be stressed that the mean yield pressure from the in-die Heckel analysis can be used as a reliable plasticity parameter: the lower the Py, the greater the degree of plasticity of the material [8].
Possessing information about the Py of each ingredient in the blend allows predicting the sequence of the events of the material irreversible deformations upon tableting cycle. Consequently, the targeted composition of a tableting blend based on excipients’ Py can predetermine the deformation (the extent of deformation) of the specific ingredients in this blend upon tableting at a specific compaction pressure [9]. Considering the possibility of undesirable solid-state polymorphic transition of the drug [10,11], particle fragmentation, the loss of coated pellet integrity [12,13], and the decreased viability and vitality of microorganisms [14,15] as a function of compaction pressure, the above-mentioned circumstances are of particular interest.
Microcrystalline cellulose (MCC) is a partially depolymerised, naturally occurring polymer in the form of crystalline powder or spheroids composed of porous particles [16], and it is one of the most commonly used excipients in tablet formulations [17]. MCC is used for direct compression (up to 90 wt.%), dried granulation/roll-compaction, and wet granulation to achieve tablets with desirable mechanical and biopharmaceutical properties [3,10,16]. MCC is recognised as an excipient with relatively low Py that undergoes plastic deformation at relatively low compression forces [3].
The effect of water on the plasticization of the MCC as well as its effect on the compaction properties upon tableting has been previously reported [18,19,20]. To the best of our knowledge, the information regarding MCC plasticization with other solvents or excipients in order to influence the compaction properties upon tableting is lacking. Nevertheless, the practice of modulating cellulose derivatives plasticity for film forming [21,22], hot-melt extrusion, and/or fusion deposition modelling 3D-printing [23,24] is common practice. While solubility parameters were found to be a useful instrument for plasticizer pre-screening [24,25].
This study aims to increase the plasticity (to reduce the Py) of MCC by loading it with a specially selected (based on the solubility parameters) plasticizer. It was assumed that a lower Py of the MCC could enable tablets to be prepared at lower compaction pressure and decrease the undesirable effect of compaction pressure.
2. Materials and Methods
2.1. Materials
CELLETS® 500 MCC cores (lot# 21E1034; IPC Process-Center GmbH & Co KG, Grunaer Weg, Germany) were used as the starting cores. The rest of the chemicals used for the experiment, such as diethyl citrate (DEC), glycerol, and methanol were of Pharmacopeia grade and used as received.
2.2. Theoretical Solubility Parameter Computation
The drug–polymer miscibility was assessed theoretically via calculations of Hansen solubility parameters (HSPs) via the group contributions methodology. Thus, the energies of dispersion forces (Ed), polar forces (Ep), and hydrogen bonding (Eh) gave the dispersion (δd), polar (δp), and hydrogen bonding (δh) partial solubility parameters, respectively [26,27].
All calculations were performed using the Hansen Solubility Parameters in Practice (HSPiP) software (5th edition, version 5.1.03). In this study, we calculated HSPs for cellulose and DEC, while HSPs for water and glycerol were taken from the software database. It should be noted that the HSPiP database includes three sets of HSPs for water: one of them is derived from the energy of vaporisation of water at 25 °C and relates to a single molecule, whereas the other two relate to six-molecule associates which are more typical for water in a liquid state [28]. In this regard, the set of HSPs for water as associated units (based on a correlation of total miscibility with certain solvents) were used in this study.
HSPs for cellulose and DEC were calculated using the following HSPiP software DIY methods: the Yamamoto-molecular break (Y-MB), in which the components were input as simplified molecular input line entry syntax (SMILES) codes; the Van Krevelen method where the components were entered by accounting for chemical constituents and taking molar volumes from Y-MB calculations; and the Hoy method with similar input procedure as the latter one. Finally, the average HSP values within all three methods were determined.
The assessment of MCC–plasticizer miscibility was accomplished by comparing HSPs calculated according to three approaches that are based on the principle ‘like dissolves like’ [29].
The approach authored by Van Krevelen and Hoftyzer estimates a high likelihood of successful mixing of two substances if the parameter ΔδT (Equation (1)) is not more than 5 MPa0.5, while complete immiscibility occurs when ΔδT exceeds 10 MPa0.5 [30,31].
By Bagley’s approach, the drug–polymer miscibility is evaluated using the combined solubility parameter δv (Equation (2)).
δv = (δd2 + δp2)0.5
The probability of miscibility is concluded if the distance between two points in the two-dimensional plot is D12 ≤ 5.0 (Equation (3)) [31].
D12 = ((δv1 − δv2)2 + (δh1 − δh2)2)0.5
The approach by Greenhalgh evaluates the miscibility as the absolute difference Δδt (Equation (4)) between the total solubility parameters δt which are calculated from Equation (5).
Δδt = |δt1 − δt2|
δt = (δd2 + δp2 + δh2)0.5
According to the latter approach, drug–polymer miscibility was assumed to be likely if Δδt ≤ 7, while Δδt ≥ 10 MPa0.5 indicated immiscibility [27].
2.3. Plasticizer Loading onto MCC Cores Using Solvent Evaporation Method
To obtain glycerol- and DEC-loaded MCC spheres, the initial MCC spheres were dried in a vacuum oven, and their water content after drying was confirmed by Karl-Fisher (V10S; Mettler-Toledo GmbH, Greifensee, Switzerland) titration at the level of 0.1 wt.%. Two batches of plasticizer-loaded MCC spheres were made, one with DEC, using methanol as a solvent, and another with glycerol, using water as a solvent (Table 1).
Table 1. Used amounts of plasticizer and solvent for the plasticizer loading procedure.
About 150 g of MCC was weighed in a 500 mL round-bottom flask. Afterwards, the amount of solvent was calculated using the MCC/solvent ratio obtained from the MCC solvent absorption test. The excess solvent amount (that which could be absorbed and adsorbed by the MCC sphere) was used. The appropriate amount of plasticizer to achieve 5% loading was dissolved in the solvent. The plasticizer solution was added to MCC in a round-bottom flask (total volume of about 250 mL) and shaken vigorously by hand. The solvent was removed by a rotary evaporator (RV3 eco, from IKA-Werke GmbH & Co. KG, Staufen, Germany) at 50 °C under a pressure of 100 mbar. After that, each sample was additionally dried with dry air (50 m3/h) in a fluid-bed drier (Mini-Glatt; Glatt GmbH, Binzen, Germany) at 50 °C until constant outlet air temperature.
2.4. Thermogravimetric Analysis (TGA)
The thermal behaviour of the samples was examined using Thermal Advantage Q50 TGA (TA Instruments, New Castle, DE, USA). The samples (5–10 mg) were heated in an open aluminium pan at a heating rate of 5 °C/min or 50 °C/min from room temperature to 350 °C. Nitrogen was used as a purge gas at a flow rate of 50 mL/min for all TGA experiments. The weight remaining (%) was plotted as a function of temperature (°C). The weight loss (dM) between starting/room temperature (RT) and 200 ℃ (RT-200 °C) and temperature onset of degradation (Td onset) were determined for each formulation. Data was processed with a Universal V4.5A software (TA Instruments, USA) [32].
2.5. Differential Scanning Calorimetry (DSC)
To investigate the thermal properties of the sample before and after processing, a heat-flux DSC (DSC Q20; TA Instruments, USA) was conducted to characterise thermal behaviour. For measurement, the samples were weighed (5–8 mg) into aluminium DSC pans and heated from −10 °C to 390 °C at 50 °C/min with a continuous purge of nitrogen gas at 50 mL/min. Melting temperature onset (Tm onset), melting peak temperature (Tm peak), and melting enthalpy were determined for each formulation. The data were processed with Universal V4.5A software (TA Instruments, USA) [10].
2.6. Powder X-ray Diffraction (pXRD) Analysis
The study was conducted on a diffractometer (RigakuTM Miniflex 600 C; Rigaku Co., Tokyo, Japan) in θ/2θ geometry at ambient temperature using CuKα X-radiation (λ = 1.54182 Å) at 40 kV and 15 mA power. X-ray diffraction patterns were collected over the 2θ range of 3–60° at a 5°/min scan rate. The ground sample was applied to the low-background silicone sample holder.
2.7. Fourier-Transform Infrared (FTIR) Attenuated Total Reflectance (ATR) Spectroscopy
FTIR-ATR study of the samples was performed on a FTIR Spectrometer (Nicolete IS20, Thermo Scientific, Karlsruhe, Germany) using a diamond prism by scanning from 4000 to 400 cm−1, with 2.0 cm−1 resolution and 100 scans per spectrum (the background was taken before each sample). Every graphically represented FTIR-profile was obtained by averaging 3 spectra.
2.8. Scanning Electron Microscopy (SEM) and Particle Size Distribution Analysis
SEM pictures were captured with a microscope (TM3030; Hitachi High-Tech Corp., Tokyo, Japan) in a vacuumed environment at 15 kV to obtain information about morphology on a microscopic level. The particle size distribution (D10%, D50%, and D90%) of the MCC spheres was determined using image analysis coupled with a VIBRI feeder and a RODOS disperser (series QICPIC/L02; Sympatec GmbH, Clausthal-Zellerfeld, Germany).
2.9. Preparation of Tablets
The samples (Table 2) were tableted with 11.28 mm flat punches to obtain a target mass of 500 mg using the compaction simulator STYL’One Nano (Medelpharm, Beynost, France/Korsch, Berlin, Germany). Compression cycles of a small rotary press with a turret diameter of 180 mm, a precompression roll diameter of 44 mm, an angle between rollers of 65 degrees, a compression roll diameter of 160 mm, an angle between main compression and the beginning of the compression ramp of 60 degrees, an angle of the ejection ramp of 20 degrees at a tableting speed of 70 rpm (maximum for STYL’One Nano), a precompression and compression forces of 5 and 30 kN (equivalent of 50 and 300 MPa) were used [9].
Table 2. Formulations for tableting.
2.10. The Theoretical True Density Calculation
The theoretical true density of tablet composition was calculated based on the pycnometric density (ρt) of MCC (1.586 g/cm3) [16,33], glycerol (1.262 g/cm3) [34], DEC (1.287 g/cm3) [35], and their shares (x, w/w) using the additive methodology and the following equation [1]:
𝜌𝑡=(𝜌𝑀𝐶𝐶×𝑥𝑀𝐶𝐶)+(𝜌𝑒𝑥𝑐×𝑥𝑒𝑥𝑐)ρt=ρMCC×xMCC+ρexc×xexc
2.11. In-Die Heckel Plot Construction
The relative density (ln(1/ε)) was calculated automatically with Alix software ver. 20220711 (Medelpharm, Beynost, France) [4]. The relative density and compaction pressure (P, MPa) data were plotted by the Heckel relationship [6]:
where: K is the slope of the linear region (the proportionality constant), and ln(1/ε0) is a constant, A, that represents the intercept/ degree of packing (at porosity ε0) achieved at low pressure because of the rearrangement process before an appreciable amount of interparticle bonding takes place. The mean yield pressure (Py, MPa) was calculated in accordance with Hersey and Rees by the equation [3,7,36]:
𝑃𝑦=1𝐾Py=1K
The mean yield pressure was measured (n = 10 for each formulation) in the pressure range between 70 and 210 MPa. A one-way ANOVA (analysis of variance) test was used to compare the means of two groups using the built-in possibilities of the current version of Excel (Microsoft 365; Redmond, Washington, DC, USA; Supplementary Materials).
3. Results and Discussion
MCC is manufactured by hydrolysis with dilute mineral acid solutions of α-cellulose sourced from raw plant material. After hydrolysis, the hydrocellulose is filtered, and the aqueous slurry is spray-dried. Thus, the MCC as an excipient contains up to 7 wt.% of moisture in accordance with pharmacopoeia (JP, PhEur, and USP) [16]. Theoretical solubility parameters were used to obtain three values (ΔδT, D12, and Δδt) to assess the possible miscibility of cellulose with water, glycerol, and DEC (Table 3, Figure 2).
Figure 2. Evaluation of MCC–plasticizer miscibility using averaged solubility parameters: 3D approach authored by Hoftyzer and Van Krevelen (a), 2D Bagley’s plot (b), and 1D bar graph according to Greenhalgh (c).
According to values averaged from the Y-MB, VK, and Hoy methods, the possible miscibility of all three plasticizers (below the proposed threshold; Table 2) was predicted only by Greenhalgh’s approach (based on Δδt calculation) which showed the following miscibility likeliness order: water > glycerol > DEC. At the same time, the other two approaches authored by Van Krevelen and Bagley, respectively, indicated that possible miscibility fell into an ambiguous region between 5 and 10 MPa0.5 for all studied plasticizers; however, the same likeliness order (glycerol > water > DEC) was established for both of them.
Therefore, the batch of dried non-plasticized (Figure 3) and three batches of glycerol-, water-, and DEC-loaded MCC spheres were used. Plasticizer-loaded MCC spheres contained 5.0 wt.% of water, 4.2 wt.% of glycerol, and 5.2 wt.% of DEC (Table 4, Figure 4).
Figure 3. SEM of MCC spheres (D10% = 563 µm, D50% = 651 µm, and D90% = 696 µm).
Figure 4. FTIR spectrum of dried and loaded MCC spheres in the range of 4000–500 cm−1.
Table 4. The summary of thermal properties determined by TGA and DSC.
The dried and plasticizer-loaded MCC-spheres were investigated with FTIR spectroscopy (Figure 4). All obtained FTIR spectra showed the characteristic vibration peaks of cellulose [37,38,39,40,41,42]:
The broad peak at 3333 cm−1 which is assigned to O–H stretching vibrations of the intermolecularly bonded hydroxyl group;
The peak at 2891 cm−1 that corresponds to C–H stretching vibrations;
The peak at 1645 cm−1 which is indicative of the O–H bending of bound water;
The multiple absorbance bands (peaks at 1428, 1368, 1334, and 1316 cm−1) assigned to the bending and stretching vibrations of C–H and C–O bonds;
The peaks at 1202, 1052, and 1021 cm−1 are assigned to the elongation of C-O bonds;
The peaks at 1158 and 897 cm−1 are due to the C–O–C stretching vibrations at the β-glycosidic linkage.
No evident differences were observed in the spectrum of water-plasticized MCC spheres compared to the dried non-plasticized sample. This could be explained by the remaining bound water in all samples even after drying (as evidenced by the persistence of the peak at 1645 cm−1 in all obtained spectra [37,41,42]. Nonetheless, some changes were established for MCC spheres treated with DEC and glycerol. Both these plasticizers led to the manifestation of the peak at ~1104 cm−1, which could be related to the stretching vibrations of the C–O bond in the ester group of DEC and the secondary alcohol group of glycerol [43,44,45]. In addition, the spectrum of DEC-loaded MCC spheres demonstrated the most explicit deviation from that of the dried MCC spheres that manifested as a peak at 1731 cm−1 which was absent in the spectra of all other three samples. This peak could be assigned to the C=O stretching of the ester functional group [43]. Therefore, it can be suggested that treatment of MCC spheres with DEC and glycerol resulted in intermolecular hydrogen bonding between hydroxyl groups of cellulose (hydrogen donor) and mentioned functional groups of these plasticizers (hydrogen acceptors), and thus, at the molecular level, the plasticization could be caused by a weakening of intermolecular hydrogen bonds between adjacent cellulose chains [46]. It is interesting to note that it was the secondary alcohol hydroxy group of glycerol (at 1103 cm−1), and not the primary ones (at ~1030 cm−1) [45], that appeared in the spectrum of the glycerol-loaded MCC. As a rule, glycerol primary hydroxy groups are more reactive, and because of that, they are more likely to be involved in homo-intermolecular hydrogen bonding (i.e., glycerol–glycerol). With loading into MCC spheres, hetero-intermolecular hydrogen bonding occurred, i.e., cellulose–glycerol, which apparently was mostly contributed by the secondary alcohol hydroxy group of glycerol, while the homo-glycerol hydrogen bonding network could be preserved. Analogue findings were demonstrated in the study of the glycerol–choline eutectic mixture, which was found to have homo-molecular glycerol hydrogen bonding network similar to that in pure glycerol, whereas choline bonds were at the interstitial voids of the glycerol network [47].
pXRD is a complementary technique to DSC and was used in assessing the presence of crystalline content in formulations. Thus, the pXRD profiles of dried and plasticizer-loaded MCC spheres were investigated. The diffraction patterns of all samples confirmed the crystalline nature of each sample with the same characteristic peaks (Figure 5). The characteristic MCC peaks were also shown to be similar to that reported in the literature [48]. Unfortunately, the pXRD method was reported to have relatively low sensitivity and a limit of detectability (LoD) of 5% [49,50]. Thus, considering the plasticizer load (approx. 5%), the pXRD profiles obtained can be considered similar (with approximately the same level of crystallinity).
Figure 5. pXRD diffractograms of dried and loaded MCC spheres.
At a 5 °C/min heating rate, the onset of degradation temperature (Td onset) increased from water to DEC and glycerol (from 297.4 to 303.2 and 309.2 °C, respectively; Table 4, Figure 3). Melting of the MCC (DSC-curves) was observed upon its degradation (TGA-curve; Table 4, Figure 4). The increase in heating rate up to 50 °C/min made it possible to increase the Td onset for water-loaded MCC up to 345.7 °C and compare the melting onset temperatures (Tm onset) for MCC loaded with plasticizers. The part of the DSC curve that described melting demonstrated a two-step shape and was characterized by two Tm onsets. The increase in Tm onset 1 and Tm onset 2 was in the same sequence and increased from water to DEC and glycerol: 291.9, 305.7, 315.8 °C for Tm onset 1 and 325.6, 332.4, 335.6 °C for Tm onset 2, respectively (Table 4, Figure 6).
Figure 6. Weight loss as a function of temperature for loaded MCC spheres (TGA at 5 °C/min).
In this study, the Tm onset 1 and 2 (for water- and DEC-loaded samples) was associated with the thermal degradation of MCC [51]. That can be observed by comparing the first derivative of weight loss and respective Tm onset on the DSC profile of water-loaded MCC spheres (Figure 7). The increase in apparent melting peak temperature (Tm) and apparent melting enthalpy can be explained with the increase in Td from water to DEC and glycerol. Therefore, the thermal analysis did not provide us with insights regarding the plasticization of MCC with selected plasticizers.
Figure 7. Heat flow as function of temperature for loaded MCC spheres (DSC at 50 °C/min; left Y-axis); the first derivative of weight loss as a function of temperature for water-loaded MCC spheres (TGA at 50 °C/min; right Y-axis).
Tableting of plasticizer-loaded MCC spheres with a compaction simulator was illustrated with pressure-displacement profiles (Figure 8a; exemplified with glycerol-loaded MCC spheres), which were converted to in-die Heckel plots (Figure 8b).
Figure 8. In-die Heckel plot (a) and pressure-displacement profile (b) for MCC spheres (CELLETS® 500) loaded with glycerol.
The mean yield pressure (Py) of non-plasticized MCC was found at the level of 136.5 ± 6.9 MPa (Av. ± S.D.). Despite the sequence of Tm onsets, the mean yield pressure of plasticizer-loaded MCC spheres decreased from DEC (124.7 ± 9.2 MPa) to water (106.6 ± 10.0 MPa) and glycerol (99.9 ± 1.9 MPa; Figure 9, Table 5). That coincided with the miscibility likelihood order based on the HSP calculations. Therefore DEC, water, and glycerol were able to decrease the Py of non-plasticized MCC spheres by 4.7, 16.3, and 38.9%, respectively.
Figure 9. Comparison of non-plasticized (dried) with plasticized MCC spheres (Cellets® 500) in terms of Py (a plasticity parameter).
Table 5.Py data statistics.
Interestingly, despite FTIR revealing more hydrogen binding sites in the case of treatment with DEC (i.e., both C–O and C=O bonds of the ester functional group), glycerol with only one binding site (C–O bond of the alcohol group) was superior in its plasticizing ability, implying that MCC–glycerol hydrogen bonding was more efficient. This could be explained from the viewpoint of molecular weights of glycerol and DEC (92.09 and 248.23 g/mol, respectively). Considering an equal mass loading of both plasticizers (7.88 g), the loading of glycerol was 2.5 times higher in terms of molarity; therefore, more molecules of plasticizer were involved and, accordingly, more hydrogen bonds with cellulose could be formed in the case of glycerol. This follows the general logic that the smaller the molecule weight, the greater the plasticization effect of the plasticizer upon the polymer matrix [52]; however, the strength of intermolecular interactions should also be considered.
Water, as an MCC plasticizer, showed a relatively high ability to decrease Py (increase plasticity). The results obtained highlight the importance of water content in the raw MCC material. Changing the MCC plasticity by 16.3% (at 5 wt.%) significantly changed the mechanical properties. Thus, the fluctuation of moisture content in the MCC (even in the eligible pharmacopeial range) can be the reason for the variability of mechanical properties in complex tablet formulations [53]. Considering moisture as one of the most important factors in pharmaceutical tablets’ shelf-life, narrow specification of moisture content in MCC during the product development stage can be recommended.
4. Conclusions
This study showed the possibility of increasing the plasticity of MCC by loading it with a deliberately chosen plasticizer. The computational approaches based on solubility parameters were found to be useful in predicting the plasticizing efficacy. Based on FTIR findings, it is suggested that plasticization resulted from intermolecular hydrogen bonding between the plasticizers and cellulose molecules that caused the weakening of hydrogen bonds between adjacent cellulose chains. At the plasticizer load used (approx. 5 wt.%), neither pXRD nor DSC gave any insights on the plasticization of MCC with selected plasticizers. Because of the relatively high plasticization ability of water towards cellulose and thus potential changes in MCC mechanical properties, narrow specification of moisture content in MCC during the product development stage can be recommended.
Additonal information on: Plasticity of Microcrystalline Cellulose Spheres
Methodology, formal analysis, investigation, data curation: V.M. and A.P.; visualization, writing—original draft preparation, writing—review and editing: A.P., T.K. and V.M.; conceptualization and supervision: V.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Acknowledgments
We would like to acknowledge the following people and their organisations for support of this project with pharmaceutical excipients. Business development manager Bastian Arlt (Glatt Pharmaceutical Services GmbH & Co. KG, Binzen, Germany) and head of business unit pharma Mandy Rehländer (HARKE Pharma GmbH, Mülheim an der Ruhr, Germany) for providing the CELLETS® 500-grade MCC spheres. We want to thank our colleagues Kirils Kukuls and Zoltán Márk Horváth for the data obtained with the compaction simulator and the improvement of the written English of this work, respectively. The author Tetiana Kolisnyk expresses a deep gratitude to the British Academy and Council for At-Risk Academics (UK) for the general and financial support in the frame of the Researchers-At-Risk program.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Lisence
The article “The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer” is published under Creative Common CC BY license. Any part of the article may be reused without permission provided that the original article is clearly cited. Reuse of an article does not imply endorsement by the authors or MDPI.
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https://cellets.com/wp-content/uploads/2024/08/fig-3.jpg19552445Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2024-08-07 14:34:022024-08-07 16:44:55The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer
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).
https://cellets.com/wp-content/uploads/2024/04/Anmerkung-2024-04-25-155250.png838590Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2024-04-24 16:26:032024-04-25 16:31:42Modelling the disintegration of pharmaceutical tablets: integrating a single particle swelling model with the discrete element method
https://cellets.com/wp-content/uploads/2022/09/parameter-titelbild.png6271200Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2023-08-22 09:15:152023-08-23 08:21:33Critical aspects of starter spheres in oral pellet formulations one should consider
https://cellets.com/wp-content/uploads/2022/02/Cellets_BCS_class_I.png6621394Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2022-02-17 15:10:072022-07-19 11:27:16BSC Class I APIs in oral formulations
Multidimensional Correlation of Surface Smoothness and Process Conditions is a necessary attempt to better understand, optimize and outperform process steps of drug formulations. Particle coating and layering in a fluidized bed process is a main attempt in pharmaceutical industry for drug production for modern oral dosage forms. The precise knowledge of control process parameters leads to high surface control of the drug-loaded particles and therefore is crucial for the quality and yield of production in a more general aspect. This application note presents a multidimensional attempt by Orth et al. [1] to correlate particle surface structure morphology and process conditions in a fluidized bed layering spray granulation. CELLETS® 500 are used as spherical, high-quality starter cores.
About fluidized bed process conditions
Fluidized bed processes are used in pharmaceutical, food and agro industries. Solid particles are transported in a defined gas stream inducing fluidized bed conditions. Solid-containing dispersions or liquids are sprayed onto the fluidized particles. Variable settings of process parameters allow particle layering, coating, coalescence and agglomeration. This point seems to make the fluidized bed becoming a universal process for particle processing, but also requests deeper knowledge about the desired process parameter settings: The goal is a stable, high-quality, high-output process.
Standard process parameters are:
liquid spray rate (m1)
fluidization air flow rate (Vair)
fluidization air temperature (Tin)
spray air temperature (Tat)
spray atomization pressure (pat)
Beside the spraying process, also the drying process plays an important role. By drying, moisture, sticky conditions and flowability are strongly influenced. Hampel [2] analyzed in her doctoral thesis the importance of the drying process using CELLETS® 200 as model particles.
Technology, Materials and Analysis
The coating experiments were carried out in a ProCell® 5 LabSystem with the fluidized bed process chamber GF3 (Glatt GmbH, Germany) as shown in Figure 1. The ProCell® 5 LabSystem is designed for testing of spouted bed and fluidized bed processes in the single kg-scale.
Fig.1: Sketch of the experimental fluidized bed setup (Procell® 5 LabSystem with GF3 chamber).
As Materials, pellets made of 100% microcrystalline cellulose (CELLETS® 500) are employed as perfect starter cores. These pellets provide smooth and defined surface properties, chemical inertness, robustness and a high degree of sphericity. Specific properties of CELLETS® 500 for this study are shown in Table 1. The roughness is at 1.5 µm and therefore delivers perfect initial conditions for controlled spray granulation.
Property
Value
Sauter diameter
639 µm
Sphericity
0.96
Surface roughness
1.5 µm
Solid density
1.445 g/cm3
Table 1: Properties of CELLETS® 500.
As spray liquid, a 30 wt% sodium benzoate solution was injected into the process chamber. The mass ratio of spray liquid to starter cores was 1:2. Different coating conditions have statistically been driven. In turn, the spray-coated particles show different surface structures (Figure 2a-d).
Fig.2a: SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (bold).
Fig. 2b: Close-up SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (bold).
Fig. 2c: SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (italic).
Fig. 2d: Close-up SEM images of CELLETS® 500 particles coated with sodium benzoate at process conditions as printed in Table 2 (italic).
Parameter
Controlled values
liquid spray rate (m1)
10 | 15 | 20
fluidization air flow rate (Vair)
80 | 105 | 130
fluidization air temperature (Tin)
50 | 85 | 120
spray air temperature (Tat)
20 | 70 | 120
spray atomization pressure (pat)
0.5 | 1.75 | 3.0
Table 2: Process parameters and values used in coating experiments.
The coated particles were analyzed regarding their surface roughness via laser scanning microscopy (VK-X160K, Keyence, Japan). Additional images were obtained with a scanning electron microscope (Supra VP55, Zeiss, Germany).
A 3D-profile of the particle surface was created and evaluated in a defined measurement area. Roughness analysis can be performed through several parameters as defined in DIN EN ISO 4287:2010-07 (2010) and DIN EN ISO 25178-2:2012 (2012). In this attempt, the arithmetical mean height was used as roughness quantifier. The roughness was correlated to the process parameters and the resulting linear correlation was rigorously analyzed using a principal component analysis.
Results
A linear regression model is fitted to the roughness data using the ordinary least squares method. This enables to create a linear model connecting the chosen process parameters to the surface roughness of the coated particles. It is mentionable, that in this attempt the fluidization air flow rate and the spray air temperature did not show a significant effect on the surface structure and were therefore removed from the model.
Process conditions: Influence of the liquid spray rate
Figure 3: Surface roughness versus liquid spray rate. The crosses mark the experimentally investigated spray rates; line represents a linear interpolation.
The dependence of the surface roughness on the spray rate of the sodium benzoate solution is shown in Figure 3. A slight increase of surface roughness is identified for increasing spray rates. The main effect is considered to be influenced by the crystallization of sodium benzoate. Following, crystallization is higher at higher spray rates caused by lower evaporation due to higher liquid volumes in the process. The dependence of the crystallization of sodium benzoate on the drying conditions during fluidized bed coating was also observed by Rieck et al. [3] and Hoffmann et al. [4].
Process conditions: Influence of the fluidization air inlet temperature
Figure 4: Surface roughness versus fluidization air inlet temperature. The crosses mark the experimentally investigated temperatures; line represents a linear interpolation.
An increase in the fluidization air inlet temperature results in a lower roughness of the coated particles and therefore in a smoother particle surface. The temperature of the fluidization air has a major impact on the drying conditions during the spray granulation process. As an increased temperature causes reduced relative humidity, the heated air can absorb a larger amount of water, which results in a high drying rate. Crystal growth of spray droplets is reduced by fast evaporation times and short drying times.
Process conditions: Influence of the atomization pressure
Figure 5: Surface roughness versus spray atomization pressure. The crosses mark the experimentally investigated pressures; line represents a linear interpolation.
With increasing atomization pressure from 0.5 bar to 3.0 bar, the surface roughness is decreasing. The pressure of the spray air strongly influences the droplet size and velocity. With increasing atomization pressure, the droplet size and size distribution decreases while the droplet velocity increases which in causes a more homogeneous spreading and promotes smoother surface coatings.
Summary
CELLETS® 500 are used as model particles for analyzing the surface roughness of coated particles dependent on process conditions in a bottom-spray process. As the results suggest, a high surface roughness is achieved at low fluidization air temperatures, low atomization pressures and high spray rates of the coating solution. Conversely, at high air temperatures, high spray pressures and low liquid spray rates, particles with smooth and compact surfaces are produced.
Acknowledgement
Prof. Stefan Heinrich and his team are gratefully acknowledged for serving content for this note:
Hamburg University of Technology Institute of Solids Process Engineering and Particle Technology
Contact: Prof. Dr. Stefan Heinrich
Denickestrasse 15, 21073 Hamburg, Germany
Tel: +49 40 42878 3750
E-mail: stefan.heinrich@tuhh.de
Website: https://www.tuhh.de/spe/
https://cellets.com/wp-content/uploads/2021/10/Fig.2b.jpg7681024Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2021-10-29 17:56:242022-07-27 13:34:48Multidimensional Correlation of Surface Smoothness and Process Conditions
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