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Pharmaceutics
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New Trends in Freeze-Drying of Pharmaceutical Products
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New Trends in Freeze-Drying of Pharmaceutical Products

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (20 April 2022) | Viewed by 39271

Special Issue Editors

Prof. Dr. Davide Fissore

E-Mail Website
Guest Editor
Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, 10138 Torino, Italy
Interests: process monitoring; process control; optimization; process analytical technologies; freeze-drying; nanoparticles
Prof. Dr. Roberto Pisano

E-Mail Website1 Website2
Co-Guest Editor
Department of Applied Science and Technology, Politecnico di Torino, IT-10129 Torino, Italy
Interests: pharmaceutical manufacturing; formulation design; drug products; mathematical modeling; molecular simulations; process analytical technologies; process control; optimization; downstream processes; liquid chromatography; continuous manufacturing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Freeze-drying plays a key role in the production process of several pharmaceutical and biopharmaceutical products, and its relevance will raise in the following years due to the continuously increasing number of biopharmaceutical products, vaccines, etc. expected to arrive to the market. Despite the batch process, carried out almost without monitoring and, quite often, with no optimization of the operating conditions, is still the standard in many companies, several innovations have been proposed in recent years. Research has been focused on several topics, e.g. (i) to accelerate the process, both primary and secondary drying (e.g. by using suitable controllers), (ii) to optimize the freezing stage (e.g. by using controlled nucleation), (iii) to monitor the process through suitable process analytical technology, (iv) to speed-up the stage of process design (e.g. by using mathematical modeling or small-scale freeze-dryers), (v) by introducing new equipment to carry out the process (e.g. in a continuous way), (vi) by introducing rational approaches to formulation development (e.g. by molecular simulation), etc.

This Special Issue will thus aim to focus on the main innovations being developed in the field of freeze-drying of pharmaceutical products. Topics may include, but are not limited to:

  • non-invasive monitoring of freeze-drying process
  • new ways to develop a freeze-drying process
  • freeze-drying of mRNA-based vaccines and other products (e.g. highly concentrated formulations)
  • continuous freeze-drying
  • rational design of formulation
  • new equipment and/or processing routes to freeze-dry a product
  • investigation and optimization of the freezing-stage

Submission of original research work or review articles is equally welcome.

Prof. Dr. Davide Fissore
Prof. Dr. Roberto Pisano
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • freeze-drying
  • process analytical technology
  • process optimization
  • process control
  • continuous manufacturing
  • protein stability
  • reconstitution time
  • highly concentrated formulations

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Published Papers (13 papers)

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Editorial

Jump to: Research, Review

3 pages, 195 KiB  
Editorial
New Trends in Freeze-Drying of Pharmaceutical Products
by Roberto Pisano and Davide Fissore
Pharmaceutics 2023, 15(7), 1975; https://doi.org/10.3390/pharmaceutics15071975 - 19 Jul 2023
Cited by 1 | Viewed by 1521
Abstract
Freeze-drying, also known as lyophilization, is a process that facilitates the removal of water through sublimation from a frozen product (primary drying) [...] Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)

Research

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15 pages, 3681 KiB  
Article
Experimental Study of the Impact of Pore Structure on Drying Kinetics and Sublimation Front Patterns
by Maximilian Thomik, Sebastian Gruber, Anders Kaestner, Petra Foerst, Evangelos Tsotsas and Nicole Vorhauer-Huget
Pharmaceutics 2022, 14(8), 1538; https://doi.org/10.3390/pharmaceutics14081538 - 23 Jul 2022
Cited by 8 | Viewed by 2253
Abstract
Freeze-drying frozen maltodextrin solutions with solid contents of 5% and 30% (w/w) was experimentally investigated using neutron imaging at PSI Villigen/Switzerland. Different solid contents, as well as annealing at −5 °C for 11 h, were used to modify the porous structure [...] Read more.
Freeze-drying frozen maltodextrin solutions with solid contents of 5% and 30% (w/w) was experimentally investigated using neutron imaging at PSI Villigen/Switzerland. Different solid contents, as well as annealing at −5 °C for 11 h, were used to modify the porous structure of the samples, which was quantified using X-ray computed tomography. Annealing of the 5% (w/w) sample, with a pore size distribution (PSD) of 23.7 ± 11.1 µm, yielded a very open pore space with high porosity (ε = 0.96) and a PSD of 33.0 ± 27.0 µm. In contrast, the higher solid content resulted in small, lamellar, narrow pores with high anisotropy and a porosity of ε = 0.65, as well as a PSD of 13.5 ± 4 µm. In operando neutron imaging was used to show the impact of the structure of frozen maltodextrin on the overall drying kinetics and shape of the sublimation front during freeze-drying. For this purpose, a freeze-drying stage was employed, which allowed a novel approach to time- and space-resolved monitoring of the ice phase. The sublimation front propagation was quantitatively analyzed based on ice saturation profiles and sublimation rates. The dependence of drying velocity on structure is nicely demonstrated by the data. In addition, it is shown that the sublimation front widened during freeze-drying, resulting in either rather concave or convex shape depending on morphological parameters. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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23 pages, 4612 KiB  
Article
Infrared Thermography for Monitoring of Freeze Drying Processes—Part 2: Monitoring of Temperature on the Surface and Vertically in Cuvettes during Freeze Drying of a Pharmaceutical Formulation
by Håkan Emteborg, Jean Charoud-Got and John Seghers
Pharmaceutics 2022, 14(5), 1007; https://doi.org/10.3390/pharmaceutics14051007 - 7 May 2022
Cited by 5 | Viewed by 1859
Abstract
The coupling of an infrared (IR) camera to a freeze dryer for monitoring of the temperature of a pharmaceutical formulation (sucrose/mannitol solution, 4:1%, m/m) during freeze-drying has been exploited further. The new development allows monitoring of temperatures simultaneously at the [...] Read more.
The coupling of an infrared (IR) camera to a freeze dryer for monitoring of the temperature of a pharmaceutical formulation (sucrose/mannitol solution, 4:1%, m/m) during freeze-drying has been exploited further. The new development allows monitoring of temperatures simultaneously at the surface as well as vertically, (e.g., in depth) along the side using custom-made cuvettes. The IR camera was placed on the chamber roof of a process-scale freeze dryer. Monitoring of cuvettes containing the formulation took place from above where one side of each cuvette was equipped with a germanium window. The Ge-window was placed next to an IR mirror having a 45° angle. The long-wave infrared radiation (LWIR) coming from the inside of the cuvette was reflected upwards toward the IR camera. Accurate recording of the temperature along the cuvettes’ depth profile was therefore possible. Direct imaging from −40 °C to 30 °C took place every 60 s on the surface and on the side with a 2 × 2 mm resolution per IR pixel for 45 h resulting in 2700 thermograms. Results are presented for freeze-drying of a pharmaceutical formulation as a function of time and spatially for the entire side (depth) of the cuvette. As the sublimation process was progressing, the spatial resolution (84 IR pixels for the side-view and 64 pixels for the surface-view) was more than sufficient to reveal lower temperatures deeper down in the material. The results show that the pharmaceutical formulation (a true solution at the onset) dries irregularly and that the sublimation front does not progress evenly through the material. During secondary drying, potential evaporative cooling of upper layers could be detected thanks to the high thermal and spatial resolution. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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Graphical abstract

16 pages, 7168 KiB  
Article
A NIR-Based Study of Desorption Kinetics during Continuous Spin Freeze-Drying
by Laurens Leys, Gust Nuytten, Joris Lammens, Pieter-Jan Van Bockstal, Jos Corver, Chris Vervaet and Thomas De Beer
Pharmaceutics 2021, 13(12), 2168; https://doi.org/10.3390/pharmaceutics13122168 - 16 Dec 2021
Cited by 6 | Viewed by 3226
Abstract
The pharmaceutical industry is progressing toward the development of more continuous manufacturing techniques. At the same time, the industry is striving toward more process understanding and improved process control, which requires the implementation of process analytical technology tools (PAT). For the purpose of [...] Read more.
The pharmaceutical industry is progressing toward the development of more continuous manufacturing techniques. At the same time, the industry is striving toward more process understanding and improved process control, which requires the implementation of process analytical technology tools (PAT). For the purpose of drying biopharmaceuticals, a continuous spin freeze-drying technology for unit doses was developed, which is based on creating thin layers of product by spinning the solution during the freezing step. Drying is performed under vacuum using infrared heaters to provide energy for the sublimation process. This approach reduces drying times by more than 90% compared to conventional batch freeze-drying. In this work, a new methodology is presented using near-infrared (NIR) spectroscopy to study the desorption kinetics during the secondary drying step of the continuous spin freeze-drying process. An inline PLS-based NIR calibration model to predict the residual moisture content of a standard formulation (i.e., 10% sucrose) was constructed and validated. This model was then used to evaluate the effect of different process parameters on the desorption rate. Product temperature, which was controlled by a PID feedback mechanism of the IR heaters, had the highest positive impact on the drying rate during secondary drying. Using a higher cooling rate during spin freezing was found to significantly increase the desorption rate as well. A higher filling volume had a smaller negative effect on the drying rate while the chamber pressure during drying was found to have no significant effect in the range between 10 and 30 Pa. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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16 pages, 5930 KiB  
Article
Spin Freezing and Its Impact on Pore Size, Tortuosity and Solid State
by Joris Lammens, Niloofar Moazami Goudarzi, Laurens Leys, Gust Nuytten, Pieter-Jan Van Bockstal, Chris Vervaet, Matthieu N. Boone and Thomas De Beer
Pharmaceutics 2021, 13(12), 2126; https://doi.org/10.3390/pharmaceutics13122126 - 9 Dec 2021
Cited by 14 | Viewed by 3205
Abstract
Spin freeze-drying, as a part of a continuous freeze-drying technology, is associated with a much higher drying rate and a higher level of process control in comparison with batch freeze-drying. However, the impact of the spin freezing rate on the dried product layer [...] Read more.
Spin freeze-drying, as a part of a continuous freeze-drying technology, is associated with a much higher drying rate and a higher level of process control in comparison with batch freeze-drying. However, the impact of the spin freezing rate on the dried product layer characteristics is not well understood at present. This research focuses on the relation between spin-freezing and pore size, pore shape, dried product mass transfer resistance and solid state of the dried product layer. This was thoroughly investigated via high-resolution X-ray micro-computed tomography (µCT), scanning electron microscopy (SEM), thermal imaging and solid state X-ray diffraction (XRD). It was concluded that slow spin-freezing rates resulted in the formation of highly tortuous structures with a high dried-product mass-transfer resistance, while fast spin-freezing rates resulted in lamellar structures with a low tortuosity and low dried-product mass-transfer resistance. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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Graphical abstract

22 pages, 3542 KiB  
Article
Development and Application of a Mechanistic Cooling and Freezing Model of the Spin Freezing Step within the Framework of Continuous Freeze-Drying
by Gust Nuytten, Susan Ríos Revatta, Pieter-Jan Van Bockstal, Ashish Kumar, Joris Lammens, Laurens Leys, Brecht Vanbillemont, Jos Corver, Chris Vervaet and Thomas De Beer
Pharmaceutics 2021, 13(12), 2076; https://doi.org/10.3390/pharmaceutics13122076 - 3 Dec 2021
Cited by 10 | Viewed by 3174
Abstract
During the spin freezing step of a recently developed continuous spin freeze-drying technology, glass vials are rapidly spun along their longitudinal axis. The aqueous drug formulation subsequently spreads over the inner vial wall, while a cold gas flow is used for cooling and [...] Read more.
During the spin freezing step of a recently developed continuous spin freeze-drying technology, glass vials are rapidly spun along their longitudinal axis. The aqueous drug formulation subsequently spreads over the inner vial wall, while a cold gas flow is used for cooling and freezing the product. In this work, a mechanistic model was developed describing the energy transfer during each phase of spin freezing in order to predict the vial and product temperature change over time. The uncertainty in the model input parameters was included via uncertainty analysis, while global sensitivity analysis was used to assign the uncertainty in the model output to the different sources of uncertainty in the model input. The model was verified, and the prediction interval corresponded to the vial temperature profiles obtained from experimental data, within the limits of the uncertainty interval. The uncertainty in the model prediction was mainly explained (>96% of uncertainty) by the uncertainty in the heat transfer coefficient, the gas temperature measurement, and the equilibrium temperature. The developed model was also applied in order to set and control a desired vial temperature profile during spin freezing. Applying this model in-line to a continuous freeze-drying process may alleviate some of the disadvantages related to batch freeze-drying, where control over the freezing step is generally poor. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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Graphical abstract

9 pages, 2406 KiB  
Communication
Investigating Alternative Container Formats for Lyophilization of Biological Materials Using Diphtheria Antitoxin Monoclonal Antibody as a Model Molecule
by Kiran P. Malik, Chinwe Duru, Paul Stickings, Esther Veronika Wenzel, Michael Hust and Paul Matejtschuk
Pharmaceutics 2021, 13(11), 1948; https://doi.org/10.3390/pharmaceutics13111948 - 17 Nov 2021
Cited by 1 | Viewed by 1707
Abstract
When preparing biological reference materials, the stability of the lyophilized product is critical for long-term storage, particularly in order to meet WHO International Standards, which are not assigned expiry dates but are expected to be in use for several decades. Glass ampoules are [...] Read more.
When preparing biological reference materials, the stability of the lyophilized product is critical for long-term storage, particularly in order to meet WHO International Standards, which are not assigned expiry dates but are expected to be in use for several decades. Glass ampoules are typically used by the National Institute for Biological Standards and Control (NIBSC) for the lyophilization of biological materials. More recently, a clear need has arisen for the filling of smaller volumes, for which ampoules may not be optimal. We investigated the use of plastic microtubes as an alternative container for small volume fills. In this study, a recombinant diphtheria antitoxin monoclonal antibody (DATMAB) was used as a model molecule to investigate the suitability of plastic microtubes for filling small volumes. The stability and quality of the dried material was assessed after an accelerated degradation study using a toxin neutralization test and size exclusion HPLC. While microtubes have shown some promise in the past for use in the lyophilization of some biological materials, issues with stability may arise when more labile materials are freeze-dried. We demonstrate here that the microtube format is unsuitable for ensuring the stability of this monoclonal antibody. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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16 pages, 8282 KiB  
Article
Observations on the Changing Shape of the Ice Mass and the Determination of the Sublimation End Point in Freeze-Drying: An Application for Through-Vial Impedance Spectroscopy (TVIS)
by Bhaskar Pandya, Geoff Smith, Irina Ermolina and Evgeny Polygalov
Pharmaceutics 2021, 13(11), 1835; https://doi.org/10.3390/pharmaceutics13111835 - 2 Nov 2021
Cited by 2 | Viewed by 2089
Abstract
Models for ice sublimation from a freeze-drying vial rely on the assumption of a planar ice interface up to ~25% loss of ice mass (which is difficult to qualify) whereas single-vial determinations of the sublimation endpoint (by temperature sensors) are based on the [...] Read more.
Models for ice sublimation from a freeze-drying vial rely on the assumption of a planar ice interface up to ~25% loss of ice mass (which is difficult to qualify) whereas single-vial determinations of the sublimation endpoint (by temperature sensors) are based on the point when the observed temperature reaches a plateau, which cannot differentiate between sublimation and desorption-drying. In this work, the real part capacitance of TVIS vial(s) containing frozen water (during sublimation drying) was measured at 100 kHz. This parameter C′(100 kHz) was shown to be highly sensitive to the shape and volume of the ice mass and is therefore a useful parameter for monitoring ice sublimation. By placing a digital camera in front of an isolated TVIS vial containing ice, it was possible to relate the changes in the shape of the ice mass with the changes in the trajectory of the time profile of C′(100 kHz) and determine the point of deviation from a planar ice interface and ultimately determine the point when the last vestiges of ice disappear. Thereafter, the same characteristics of the C′(100 kHz) time-profile were identified for those TVIS vials located out of sight of the camera in a separate full-shelf lyo study, thereby obviating the need for photographic examination. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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12 pages, 1762 KiB  
Article
Nanoencapsulation as a General Solution for Lyophilization of Labile Substrates
by Girish Vallerinteavide Mavelli, Samira Sadeghi, Siddhesh Sujit Vaidya, Shik Nie Kong and Chester Lee Drum
Pharmaceutics 2021, 13(11), 1790; https://doi.org/10.3390/pharmaceutics13111790 - 26 Oct 2021
Cited by 6 | Viewed by 2889
Abstract
Protein macromolecules occur naturally at the nanoscale. The use of a dedicated nanoparticle as a lyophilization excipient, however, has not been reported. Because biopolymeric and lipid nanoparticles often denature protein macromolecules and commonly lack the structural rigidity to survive the freeze-drying process, we [...] Read more.
Protein macromolecules occur naturally at the nanoscale. The use of a dedicated nanoparticle as a lyophilization excipient, however, has not been reported. Because biopolymeric and lipid nanoparticles often denature protein macromolecules and commonly lack the structural rigidity to survive the freeze-drying process, we hypothesized that surrounding an individual protein substrate with a nanoscale, thermostable exoshell (tES) would prevent aggregation and protect the substrate from denaturation during freezing, sublimation, and storage. We systematically investigated the properties of tES, including secondary structure and its homogeneity, throughout the process of lyophilization and found that tES have a near 100% recovery following aqueous reconstitution. We then tested the hypothesis that tES could encapsulate a model substrate, horseradish peroxidase (HRP), using charge complementation and pH-mediated controlled assembly. HRP were encapsulated within the 8 nm internal tES aqueous cavity using a simplified loading procedure. Time-course experiments demonstrated that unprotected HRP loses 95% of activity after 1 month of lyophilized storage. After encapsulation within tES nanoparticles, 70% of HRP activity was recovered, representing a 14-fold improvement and this effect was reproducible across a range of storage temperatures. To our knowledge, these results represent the first reported use of nanoparticle encapsulation to stabilize a functional macromolecule during lyophilization. Thermostable nanoencapsulation may be a useful method for the long-term storage of labile proteins. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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14 pages, 6164 KiB  
Article
Surface Treatment of Glass Vials for Lyophilization: Implications for Vacuum-Induced Surface Freezing
by Francesco Regis, Andrea Arsiccio, Erwan Bourlès, Bernadette Scutellà and Roberto Pisano
Pharmaceutics 2021, 13(11), 1766; https://doi.org/10.3390/pharmaceutics13111766 - 22 Oct 2021
Cited by 6 | Viewed by 4418
Abstract
Freeze-drying is commonly used to increase the shelf-life of pharmaceuticals and biopharmaceuticals. Freezing represents a crucial phase in the freeze-drying process, as it determines both cycle efficiency and product quality. For this reason, different strategies have been developed to allow for a better [...] Read more.
Freeze-drying is commonly used to increase the shelf-life of pharmaceuticals and biopharmaceuticals. Freezing represents a crucial phase in the freeze-drying process, as it determines both cycle efficiency and product quality. For this reason, different strategies have been developed to allow for a better control of freezing, among them, the so-called vacuum-induced surface freezing (VISF), which makes it possible to trigger nucleation at the same time in all the vials being processed. We studied the effect of different vial types, characterized by the presence of hydrophilic (sulfate treatment) or hydrophobic (siliconization and TopLyo Si–O–C–H layer) inner coatings, on the application of VISF. We observed that hydrophobic coatings promoted boiling and blow-up phenomena, resulting in unacceptable aesthetic defects in the final product. In contrast, hydrophilic coatings increased the risk of fogging (i.e., the undesired creeping of the product upward along the inner vial surface). We also found that the addition of a surfactant (Tween 80) to the formulation suppressed boiling in hydrophobic-coated vials, but it enhanced the formation of bubbles. This undesired bubbling events induced by the surfactant could, however, be eliminated by a degassing step prior to the application of VISF. Overall, the combination of degasification and surfactant addition seems to be a promising strategy for the successful induction of nucleation by VISF in hydrophobic vials. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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13 pages, 1367 KiB  
Article
Minimizing Oxidation of Freeze-Dried Monoclonal Antibodies in Polymeric Vials Using a Smart Packaging Approach
by Nicole Härdter, Tim Menzen and Gerhard Winter
Pharmaceutics 2021, 13(10), 1695; https://doi.org/10.3390/pharmaceutics13101695 - 15 Oct 2021
Cited by 8 | Viewed by 3558
Abstract
Primary containers made of cyclic olefin polymer (COP) have recently gained attention since they may overcome several risks and shortcomings of glass containers as they exhibit a high break resistance, biocompatibility, and homogeneous heat transfer during lyophilization. On the downside, COP is more [...] Read more.
Primary containers made of cyclic olefin polymer (COP) have recently gained attention since they may overcome several risks and shortcomings of glass containers as they exhibit a high break resistance, biocompatibility, and homogeneous heat transfer during lyophilization. On the downside, COP is more permeable for gases, which can lead to an ingress of oxygen into the container over time. Since oxidation is an important degradation pathway for monoclonal antibodies (mAbs), the continuous migration of oxygen into drug product containers should be avoided overall. To date, no long-term stability studies regarding lyophilizates in polymer vials have been published, potentially because of the unbearable gas permeability. In this study, we demonstrate that after lyophilization in COP vials and storage of these vials in aluminum pouches together with combined oxygen and moisture absorbers (“smart packaging”), oxidation of two lyophilized therapeutic antibodies was as low as in glass vials due to the deoxygenated environment in the pouch. Nevertheless, active removal of oxygen from the primary container below the initial level over time during storage in such “smart” secondary packaging was not achieved. Furthermore, residual moisture was controlled. Overall, the smart packaging reveals a promising approach for long-term stability of biopharmaceuticals; in addition to COP’s known benefits, stable, low oxygen and moisture levels as well as the protection from light and cushioning against mechanical shock by the secondary packaging preserve the sensitive products very well. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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22 pages, 44537 KiB  
Article
Investigation of the Freezing Phenomenon in Vials Using an Infrared Camera
by Maitê Harguindeguy, Lorenzo Stratta, Davide Fissore and Roberto Pisano
Pharmaceutics 2021, 13(10), 1664; https://doi.org/10.3390/pharmaceutics13101664 - 12 Oct 2021
Cited by 13 | Viewed by 2428
Abstract
The freezing phenomenon has a dramatic impact on the quality of freeze-dried products. Several freezing models applied to solutions in vials have been proposed to predict the resulting product morphology and describe heat transfer mechanisms. However, there is a lack of detailed experimental [...] Read more.
The freezing phenomenon has a dramatic impact on the quality of freeze-dried products. Several freezing models applied to solutions in vials have been proposed to predict the resulting product morphology and describe heat transfer mechanisms. However, there is a lack of detailed experimental observations of the freezing phenomenon in vials in the literature. Thus, the present work offers new experimental observations of the freezing phenomenon in vials by infrared (IR) thermography. IR imaging allowed each vial’s whole axial temperature profile to be collected during freezing, providing significant insights into the process. Spontaneous nucleation and vacuum-induced surface freezing (VISF), as a controlled nucleation technique, are investigated. Batches having vials in direct contact with the shelf (exchanging heat mainly through conduction) as well as suspended (exchanging heat mainly through natural convection and radiation) were tested. The study used three solutions: sucrose 5%, mannitol 5%, and dextran 10%. SEM images coupled with an automated image segmentation technique were also performed to examine possible correlations between the freezing observations and the resulting pore size distributions. IR thermography was found to be a promising tool for experimentally predicting the resulting product morphology in-line. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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Review

Jump to: Editorial, Research

36 pages, 5292 KiB  
Review
Calorimetric Investigation of the Relaxation Phenomena in Amorphous Lyophilized Solids
by Sebastian Groёl, Tim Menzen and Gerhard Winter
Pharmaceutics 2021, 13(10), 1735; https://doi.org/10.3390/pharmaceutics13101735 - 19 Oct 2021
Cited by 12 | Viewed by 2867
Abstract
Studying the thermal history and relaxation of solid amorphous drug product matrices by calorimetry is a well-known approach, particularly in the context of correlating the matrix parameters with the long-term stability of freeze-dried protein drug products. Such calorimetric investigations are even more relevant [...] Read more.
Studying the thermal history and relaxation of solid amorphous drug product matrices by calorimetry is a well-known approach, particularly in the context of correlating the matrix parameters with the long-term stability of freeze-dried protein drug products. Such calorimetric investigations are even more relevant today, as the application of new process techniques in freeze-drying (which strongly influence the thermal history of the products) has recently gained more interest. To revive the application of calorimetric methods, the widely scattered knowledge on this matter is condensed into a review and completed with new experimental data. The calorimetric methods are applied to recent techniques in lyophilization, such as controlled nucleation and aggressive/collapse drying. Phenomena such as pre-Tg events in differential scanning calorimetry and aging shoulders in isothermal microcalorimetry are critically reviewed and supplemented with data of freeze-dried products that have not been characterized with these methods before. Full article
(This article belongs to the Special Issue New Trends in Freeze-Drying of Pharmaceutical Products)
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